Abstract
Chemicals are measured regularly in air, food, the environment, and the workplace. Biomonitoring of chemicals in biological fluids is a tool to determine the individual exposure. Blood protein adducts of xenobiotics are a marker of both exposure and the biologically effective dose. Urinary metabolites and blood metabolites are short term exposure markers. Stable hemoglobin adducts are exposure markers of up to 120 days. Blood protein adducts are formed with many xenobiotics at different sites of the blood proteins. Newer methods apply the techniques developed in the field of proteomics. Larger adducted peptides with 20 amino acids are used for quantitation. Unfortunately, at present the methods do not reach the limits of detection obtained with the methods looking at single amino acid adducts or at chemically cleaved adducts. Therefore, to progress in the field new approaches are needed.
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Introduction
Humans are exposed to xenobiotics through air, water, food, and the environment (Fig. 1). The external dose is determined regularly for a few compounds in air, water, and food by the respective authorities. Computer models have been established to estimate the potential exposure of people (Egeghy et al. 2016). In biomonitoring programs, usually the parent compounds or their metabolites are measured in urine (LaKind et al. 2019). Such measurements are per nature highly variable due to the fast elimination of non-persistent chemicals from the body. The US-EPA (Breen et al. 2021; Dawson et al. 2021; Honda et al. 2019; Wambaugh et al. 2018) and -NIEHS (NTP, https://ice.ntp.niehs.nih.gov/) are working on models to establish a link between in vitro and in vivo data. Using the framework of adverse outcome pathways (AOP), the data obtained in vitro could be used to predict the levels in biological samples (urine, blood) that yield adverse effects in humans (in vitro to in vivo extrapolation (IVIVE)). These predicted levels could be compared to the data obtained in all major existing biomonitoring studies. In the US Centers for Disease Control (CDC)’s National Health and Nutrition Examination Survey (NHANES) studies, health-related parameters have been registered. First studies were performed to link the predicted and effective actual effects obtained mainly from the NHANES program and from medicinal drugs (Honda et al. 2019; Wambaugh et al. 2018). Pharmacological models could be compared. The method could be also applied for the prioritization of chemicals, but more work is needed. However, such evaluations should also be applied to data regarding blood protein and/or DNA adducts.
Urinary and blood levels reflect the exposure to non-persistent chemicals of the last 24–48 h. Hair levels of xenobiotics describe the exposure to xenobiotics over a longer time frame. Many chemicals become toxic only after metabolism (Fig. 2). Reactive metabolites form covalent adducts with biomolecules (glutathione, proteins, DNA). This can lead to cytotoxic and genotoxic effects. It is important for the risk assessment of chemicals to quantify the presence of reactive metabolites in the human body. Almost 50 years ago, it was shown that ethylene oxide reacts with hemoglobin and with the DNA of the target organ in a dose-dependent matter (Ehrenberg et al. 1974). Therefore, hemoglobin or albumin adducts of xenobiotics are important dosimeters to monitor the presence of toxic metabolites in the human body (Fig. 2). Stable blood protein adducts reflect the exposure history over a longer time period than do urinary metabolites, or than metabolites present in blood. Stable hemoglobin adducts have a lifetime of up to 120 days and stable albumin adducts a half-life of 20–25 days (reviewed in Sabbioni and Jones 2002; Skipper and Tannenbaum 1990; Törnqvist et al. 2002)) in humans. Reaction products with hemoglobin accumulate up to 60 times a single daily dose and albumin adducts up to 29 times a single daily dose. Blood protein adducts are excellent markers of exposure.
Albumin adduct formation is investigated to determine the potential of drugs for idiosyncratic effects (Baillie 2020; Stepan et al. 2011). Peptide and protein binding tests are included in OECD-tests to evaluate the potential skin sensitization by chemicals (OECD 2021a; OECD 2021b). In the field of occupational and environmental toxicology, binding to proteins is of interest to determine the bioavailability of reactive xenobiotics.
The 60-year story of aflatoxin B1 (AFB) is a landmark for the field of toxicology, biomonitoring, chemoprevention, and public health interventions (Kensler et al. 2011; Wogan et al. 2012). Urinary metabolites, albumin adducts, DNA adducts, immunological effects, biochemical and biological mechanisms, and associations to disease such as liver cancer were studied over decades. The determination of DNA and albumin adducts (Fig. 3) was a key step in the evolution of this research (reviewed in (Sabbioni and Sepai 1998)). Animal experiments show that albumin adducts of AFB increase linearly with the dose, as do the DNA adducts in the liver (target organ) (Wild et al. 1986) (Fig. 4). For hemoglobin adducts, the studies with ethylene oxide (Ehrenberg et al. 1974) or with 4-aminobiphenyl (Green et al. 1984) are the landmarks for molecular epidemiology studies.
Different approaches have been developed for the detection of albumin and hemoglobin adducts (Fig. 5). Before the year 2000, most methods were based on the cleavage of the adducts by base or acid. The hydrolyzed compound could then be determined by instruments available at that time. The analysis of peptide adducts was mostly performed using enzyme-linked immunosorbent assay (ELISA). As mass spectrometry developed, larger peptide adducts could be detected. In the past, the analyzed compounds were confirmed by synthetic standards. Now, researchers tend to (and at veracity’s peril) solely rely on the capabilities of mass spectrometry for the identification of compounds.
In the following, we present a short review of the progress made in regard to albumin and hemoglobin adduct determinations.
Protein adducts
Albumin adducts
In vitro reactions of albumin
For albumin, the N-terminus (aspartic acid) or different major amino acid side chains form adducts in vitro with reactive chemicals (reviewed in Goto et al. 2013; Rubino et al. 2009; Sabbioni and Turesky 2017; Tailor et al. 2016)) (Table 1). Albumin adducts of drugs (Tailor et al. 2016) (Table 1), organophosphorous compounds such as nerve agents (Golime et al. 2019) and pesticides were investigated. Especially, nerve agents were tested to discover long-term markers for nerve gas exposures (Golime et al. 2019). Drugs were tested in regard to potential adverse effects such as idiosyncratic effects (Baillie 2020; Stepan et al. 2011). In the field of environmental and occupational toxicology, albumin adducts were used as markers of exposure, of biologically effective dose for compounds causing oxidative damage, asthma, cancer, methemoglobinemia and other health effects.
In vitro modified albumin is digested with trypsin and analyzed by LC–MS/MS. The number of adducted amino acids increase with the amount of the chemical incubated with albumin. The molecular ratios used for most these experiments are far beyond the expected in vivo load of albumin. These experiments help to find eventual reactive hotspots on albumin. Sometimes, the intensity of the peaks is associated with a higher modification per mole of peptide, assuming that the detection response is the same for all molecules. The amino acids with most hits (≥ 4 different compounds, hot spots), obtained with the various compounds studied, are: Asp-1, Lys-4, Lys-12, Cys-34, His-67, Tyr-138, His-146, Lys-190, Lys-195, Lys-199, Lys-212, Lys-281, His-337, Lys-351, Lys-414, Lys-432, Lys-524, Lys-525, and Lys-541 (Table 1).
Adducts formed with albumin in vivo
For the analysis of in vivo samples, methods developed in the past used the technologies available at that time: ELISA, LC-UV, LC-FLD and GC–MS. Putative adducts were synthesized and then these adducts were searched in the in vivo samples. A very popular approach was the chemical cleavage of the adducts (Fig. 5, 6). Most adducts were cleaved by acid and/or base hydrolysis. The released chemical was extracted and analyzed for example by GC–MS (e.g., reviewed in arylamines (Sabbioni 2017)). With newer LC–MS/MS instruments, adduct analyses are performed with the detection of the intact adduct after enzymatic hydrolysis (Table. 2,3,1S). The aflatoxin B1 adduct with albumin has been part of many studies for 34 years (Groopman et al. 2008; Wogan et al. 2012). Here the typical evolution of methods took place: starting with ELISA tests, LC-UV, LC-FLD (reviewed in (Sabbioni and Sepai 1998) and LC–MS/MS (reviewed in (McCoy et al. 2008)). The sensitivity of the major albumin adduct AFB-Lys increases in the order of LC-UV, LC-FLD, ELISA and LC–MS/MS (McCoy et al. 2008). The compounds in Table 3 were ordered with ascending LOQ; it should be noted that many different definitions are used and applied for the terms LOD and LOQ (Shrivastava and Gupta 2011).
In albumin samples from humans and/or animals (Table 3, Table 1S, 2S, Fig. 6), the following compounds form an adduct with cysteine: a) environmental and occupational toxicants – benzene (Lindstrom et al. 1998; McDonald et al. 1993), pentachlorobenzene (Waidyanatha et al. 1994), styrene (Fustinoni et al. 1998), naphthalene (Waidyanatha and Rappaport 2008), acrolein (Witort et al. 2016); b) chemical warfare agents – sulfur mustard (Andacht et al. 2014), V-type nerve agents (Kranawetvogl et al. 2018); c) drugs – N-acetylaminophenol (Damsten et al. 2007); d) oxidative stress markers via cysteinylation (Regazzoni et al. 2013); e) natural products – pyrrolizidine alkaloids (Ma et al. 2019), estrogen quinones (Chen et al. 2020), aristolochic acid (Chan et al. 2021), the cooked meat carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) (Bellamri et al. 2018); f) pesticides – malathion (Yamagishi et al. 2021).
Adducts with lysines are found for: a) mycotoxins – AFB (Sabbioni 1990), aflatoxin G1 (Sabbioni and Wild 1991); b) isocyanates – 4,4’-methylenediphenyl diisocyanate (MDI) (Sabbioni et al. 2010), toluene diisocyanate (24TDI, 26TDI) (Sabbioni et al. 2012); c) isothiocyanates (ITC) derived from cruciferous vegetables – such as phenylethyl-ITC (PEITC) (Kumar and Sabbioni 2010), benzyl-ITC (BITC), allyl-ITC (AITC), and sulforaphane (SFN); d) environmental and occupational toxicants – tetrachloroethane (Pahler et al. 1999); e) oxidative stress markers – malondialdehyde (Colombo et al. 2016; Witort et al. 2016), formaldehyde (Regazzoni et al. 2017), f) endogenous compounds–glycation products (Altomare et al. 2021), and g) pesticides such as malathion (Yamagishi et al. 2021).
Adducts with tyrosines are found for: a) chemical warfare agents – sarin, soman, tabun, cyclosarin (Williams et al. 2007), tabun (Sun et al. 2017) and tabun-subtype nerve agents (Fu et al. 2019); b) pesticides – organophosphorus pesticides (von der Wellen et al. 2018), chlorpyrifos (Li et al. 2013), diazinon and dichlorvos (van der Schans et al. 2013); c) oxidative stress markers, e.g., yielding 3-nitrotyrosine (Delatour et al. 2002).
Adducts with histidines are found for: a) natural products - pyrrolizidine alkaloids (Ma et al. 2019), 1-methoxy-3-indolylmethyl glucosinolate (Barknowitz et al. 2014; Wiesner-Reinhold et al. 2019).
An adduct with tryptophan (Trp-215) was found in rodents given 4-aminobiphenyl (Skipper et al. 1985) or methleugenol (Nieschalke 2021), a natural compound of many plants.
In some in vivo studies, the levels of the same adduct type were compared between albumin and hemoglobin. In biological samples obtained after exposure to some xenobiotics, in general higher adduct levels were found in albumin than in hemoglobin: the cysteine adducts of naphthalene in mice (Waidyanatha and Rappaport 2008), the cysteine adducts of benzene in rats (Waidyanatha et al. 1998), the histidine adducts of 1‑methoxy-3-indolylmethyl isothiocyanate in mice (Barknowitz et al. 2014) (Fig. 6), the lysine adducts of isothiocyanates released from glucosinolates present in cruciferous vegetables (Kumar and Sabbioni 2010). The hydrolyzable adduct levels of arylamines are higher with hemoglobin than with albumin (Birner and Neumann 1988; Neumann et al. 1993). In contrast, for six radiolabeled arylamines tested in rodents, two had higher total adduct levels (hydrolyzable + non-hydrolyzable) with albumin than with hemoglobin.
In the newest studies, LC–MS/MS analyses after trypsin digestion is the method of choice to perform targeted and untargeted analyses (Grigoryan et al. 2016; Preston and Phillips 2019; Yano et al. 2020). However, it seems that applications are not going beyond small studies, since the detection levels of small molecules cannot be matched (Table 3). Therefore, for low level detection of chemicals more enzyme combinations were investigated to obtain shorter adducted peptides to increase the possibilities of separation of the adducted peptides from the unadducted peptides (Pathak et al. 2015). Thus, more facile enrichment and chromatographic separations of low molecular weight peptide adducts may be achieved than for the corresponding tryptic adducts, where the influence of the adduct on the logD is greatly diminished. In Table 2, the major peptides obtained with different enzymes is shown. The logD of the peptides was estimated by software.
Proteases, such as trypsin, can produce long peptides such as the T3-tryptic peptide A21LVLIAFAQYLQQCPFEDHVK41, whereas pronase digestion yields mono- di- or tripeptide Cys-containing adducts. The T3 peptide was used in most recent studies for a targeted and untargeted biomonitoring approach (Li et al. 2011; Preston et al. 2020). Combination of enzymes yields different lengths of peptides (Table 2). The logD values (pH dependent octanol–water partition coefficient) of long peptides not containing many hydrophobic amino acids are usually much smaller than the logD of smaller peptides such as CPF (Table 2). The logDs were predicted by software (www.chemaxon.com, Marvin Sketch 20.13, logP calculations in Chemaxon using the consensus mode). Such programs yield different results since for some structural features parameters are lacking. Hydrophobic adducts change the logD accordingly. The relative influence of hydrophobic adducts is larger in peptides with smaller logD values. For Cys adducts formed in longer peptides such as the T3 peptide, the logD values for 14BQ, NAPQI and nevirapine (Nevp) are -9.71, -9.25 and -8.41, respectively, (pH 4.0 = pH with the maximum level of the logD), compared to the unmodified T3 peptide with a logD of -10.4 at pH 4.0. The adducts formed of CPF (logD = -1.94) with NAPQI (NAPQI-CPF), 14BQ (14BQ-CPF) and nevirapine (Nevp-CPF) yield logD values of -1.03, -0.78 and + 0.07, respectively, at pH 5.5 (Fig. 7). Adducts of cysteine with NAPQI, 14BQ, and nevirapine yield a logD of -2.09, -1.63 and -0.78, respectively. In general, the logD of adducts which do not deprotonate or protonate in the the pH-ranges given in Table 2, increase with a constant amount in comparison to the unadducted peptides: for example for NAPQI, 14BQ and nevirapine with + 0.7, + 0.87, and + 2.01, respectively. Thus, more facile enrichment and chromatographic separations of adducts can be achieved with compounds with a higher logD. The highest logD were found for the tripeptide adducts of CPF. Other “lipophilic” hotspots (Table 1) could be for example FLK195K196YL (logD = -1.13, pH= 9.5) or LK199CA (logD = -3.4, pH = 9.0), if they can be obtained in good yield by a combination of enzymes. The mass spectrometric properties of the shorter peptides are not dominated by the large number of amino acids present in the T3 peptide. However, smaller peptide fragments do not necessarily imply higher MS response (van den Broek et al. 2013; van den Broek et al. 2007). The effect of ionization suppression by co-eluting matrix components can be minimized by having the targeted adduct with a logD different than the bulk of the other components of the digest.
Probably, the LOQ for the albumin adduct of the adducted T3 peptide (ALVLIAFAQYLQQC(-14BQ)PFEDHVK) (Smith et al. 2021) with a logD of -9.25 could be lowered significantly using other enzyme combinations yielding 14BQ-CPF or 4BQ-C with a logD of -0.78 and -1.63, respectively, if the same digestion yields are obtained. To evaluate the digestion yields synthetic standards are needed. The same applies to the LQQC(-SO2-PhIP)PFEDHVK (Pathak et al. 2015). A combination of other enzymes would yield CPF and Cys adducts with logDs of -1.03 and -1.92, respectively.
In some cases, the decrease in sensitivity for analyses with adducts in the T3 peptide was further investigated. For the analysis of MDI-albumin adducts in workers, the single amino acid adduct (MDI-Lys) released after pronase digestion can be detected at lower levels (Sabbioni et al. 2010) than the MDI-peptide fragment released after trypsin digestion (Luna et al. 2014). In the case of the albumin adduct of sulfur mustard, the adducted T3 peptide ALVLIAFAQYLQQC(S-HETE)PFEDHVK could not be found in human samples (Noort et al. 1999), whereas the C(S-HETE)PF sulfur mustard adduct, obtained by pronase digestion, was identified in humans. The same applies to the adduct of PhIP with albumin. The peptide cannot be found in vivo but only after cleavage with acid (Bellamri et al. 2018; Wang et al. 2017). This is a consequence of the much lower LOQ for the cleaved product.
Thus far, the successes in measuring albumin-carcinogen adducts in humans have largely been with those adducts that are cleaved from albumin by acid or base treatment (i.e., Cys-BQ or BAP tetraols) (Rappaport et al. 2005; Sabbioni and Turesky 2017), or by the extensive digestion of albumin with a mixture of proteases to produce mono amino acid adducts (AFB-Lys adducts) (reviewed in Sabbioni and Turesky 2017)). The physico-chemical properties of these covalently adducted amino acids or carcinogen hydrolysis products are sufficiently distinct from non-modified amino acids or peptides such that selective enrichment procedures could be developed to isolate and assay the albumin adduction products. The employment of trypsin or other specific proteases to digest albumin produces defined peptides where sites of the toxicant adduction can be precisely located by MS/MS sequencing. These types of analyses provide valuable information about the sites of adduction to albumin, which are usually lost when digestions are done by pronase or acid/base hydrolysis, unless adducts are formed and retained to the solitary Cys-34 or Trp-214 residues of albumin.
An untargeted approach has been proposed by Rappaport et al. (Chung et al. 2014; Li et al. 2011) with the analysis of the tryptic digest containing Cys-34. The interpretation of massive MS-results remains difficult. Potential new adducts were not confirmed by synthetic standards. The experiments were all carried out with adducts that were not characterized by the standards of organic chemistry. The sensitivity of the method was not sufficient.
The logD values of different adducts used for in vivo analyses are listed in Table 3. At first sight, it appears that decreasing logD values are associated with an increasing LOQ. The response of the MS detectors depends also on the co-eluting matrix, the amount of fragmentation of the molecule, the proton affinity of the molecule, the chromatography and MS instrument parameters. In the case of negative ESI, the negative charge capture features of the analyzed molecule are important. This might explain the threefold difference of LOQ between AITC-Lys and SFN-Lys (Kumar and Sabbioni 2010).
Hemoglobin adducts
In vitro reactions with hemoglobin
In comparison to albumin, not as many binding studies were performed with hemoglobin. Different specific reaction sites are known for hemoglobin (reviewed in (Rubino et al. 2009; Sabbioni 2017; Törnqvist et al. 2002)). In Table 4 and 3S, the results of the in vitro experiments are summarized. The data were obtained from tryptic digests of hemoglobin. Other enzyme combinations are possible for the analysis of hemoglobin adducts at β-Cys-93 (Table 5). As seen for albumin adducts, this might increase the sensitivity of the assay. However, the obtained fragments have very low logDs. In vitro reactions were performed with the following compounds: a) isocyanates – MDI, 24TDI; b) the reactive metabolites of occupational toxicants – styrene oxide, diepoxybutane; c) reactive metabolites of the drug – 12-mesyloxy-nevirapine as surrogate of the metabolite 12-sulfoxy-nevirapine, 16α-hydroxyestrone; d) oxidative stress markers – formaldehyde, glutathionylation, nitration, oxidation; d) skin sensitizers – 1-chloro-2,4-dinitrobenzene, 1,2-epoxy-3-phenoxypropane; e) chemical warfare agents – sulfur mustard; f) (heterocyclic) and aromatic amines – N-hydroxy-4-aminobiphenyl, N-hydroxy-aniline, 2-hydroxyamino-9H-pyrido[2,3-b]indole; g) oxidative stress markers. The main hot spots (≥ 4 hits of different compounds) are: α-Val-1, α-His-20, α-Tyr-24, α-His-45, α-Cys-104, β-Val-1, β-His-77, β-Cys-93, and β-Cys-112.
Applications with the N-terminal valine adducts
In human and animal studies (Fig. 8, Table 6, Table 3S), adducts with the N-terminal valine of hemoglobin (Carlsson et al. 2019, 2014) and with Cys-93 of the β-chain of hemoglobin (Pathak et al. 2016) were analyzed for example for alkylating agents (Törnqvist et al. 2002) and aromatic amines (reviewed in (Sabbioni 2017)), respectively. Hemoglobin was suggested for in vivo dose monitoring of alkylating agents as early as 1974 by Ehrenberg et al. (Ehrenberg et al. 1974; Osterman-Golkar et al. 1976). The method is based on the specific cleavage of adducts to N-terminal valines (alpha and beta chain) in hemoglobin (Törnqvist et al. 1986). For the GC–MS method, the globin is derivatized with pentafluorophenyl isothiocyanate (PFPITC) and after heating the adduct is cleaved from the rest of the protein. Several biomonitoring methods for the determination of N-terminal adducts of acrylamide, ethylene oxide, epichlorohydrin, glycidol, glycidamide, benzyl chloride, and others were validated in the German Working Group “Analyses in Biological Materials of the permanent Senate Commission for the Investigation of Health Hazards of Chemical Compounds in the Work” and the standard operation values are available online (https://onlinelibrary.wiley.com/doi/book/10.1002/3527600418) (Table 6). The procedures are presented in form of standard operating procedures and have been tested by other laboratories. The same derivatization with PFPITC was followed by LC–MS/MS analysis to determine the N-terminal valine adducts of acrylamide, glycidamide, and ethylene oxide (Yang et al. 2018) (Table 6, Fig. 8).
The methods using PFPITC derivatization and GC–MS have been applied for the long-term health risks after accidental exposure using hemoglobin adducts of epichlorohydrin (Wollin et al. 2014), of acrylonitrile and ethylene in 2008 (Leng and Gries 2014). Another study using the method was performed to assess the exposure of acrylonitrile in the emergency responders of a major train accident in Belgium (Van Nieuwenhuyse et al. 2014). The validity of different biomonitoring parameters including the PFPITC derivatization was used for the assessment of occupational exposure to N,N-dimethylformamide (Seitz et al. 2018). In one event where Chinese male individuals were accidentally exposed to unknown chemicals, the N-terminal valine adduct of sulfur mustard was analyzed after PFPITC-derivatized N-terminal valine using GC–MS (Xu et al. 2014). A different approach was proposed by Mráz et al. (Mráz et al. 2018). The N-(2-hydroxyethyl)valine in globin of ethylene oxide-exposed workers was analyzed using total acidic hydrolysis and LC–MS/MS analysis.
Hemoglobin adducts of acrylamide and glycidamide have been determined in the large biomonitoring study by the CDC-NHANES. In the two sampling periods 2003–4 and 2005–6, 7101 and 7857 samples obtained from non-smokers were analyzed. The LOQ of acrylamide (glycidamide) adducts for the two sampling periods was 3 (4) and 0.11 (0.66) fmol/mg hemoglobin (CDC-NHANES 2021c). Additional samples from smokers were analyzed in 2013–2014 (CDC-NHANES 2019; CDC-NHANES 2021a). For acrylamide (n = 2348) and glycidamide (n = 2149) the LODs were 0.11 and 0.67 fmol/mg hemoglobin, respectively. In 2015/2016, acrylamide (glycidamide) was measured in 2413 (2267) samples (LOD = 0.11 (0.67)). The authors of the NHANES studies used PFPITC as derivatizing agent and analyzed the compounds by LC–MS/MS (Yang et al. 2018). The detailed standard operation procedures specified as laboratory methods are available for all biomonitoring NHANES studies (CDC-NHANES 2015–16; CDC-NHANES 2021b).
The classic Edman procedure using PFPITC was developed further in the laboratory of Törnqvist. For LC–MS/MS analyses, the derivatizing agent was changed to fluorescein isothiocyanate (FITC) (Rydberg et al. 2009; von Stedingk et al. 2010, 2011). Laboratories using this method should be aware of the structural changes of the FITC-derivatives depending from the pH (Rydberg et al. 2009). The adducts were synthesized and characterized with 1H-NMR, 13C-NMR and MS for the N-methylvaline (Rydberg et al. 2009), N-(3-oxopentyl)valine (Carlsson et al. 2015), N-benzylvaline, N-(2-hydroxybenzyl)valine, N-(3-hydroxybenzyl)valine, and N-(4-hydroxybenzyl)valine (Degner et al. 2018). Now, several adducts and internal standards can be purchased (Table 6, 3S). The new method with FITC was applied for the detection of N-terminal valine adducts with: glycidamide, ethylene oxide, and acrylamide (von Stedingk et al. 2010) (Table 6, 3S); glyoxal, methylglyoxal, acrylic acid, and 1-octen-3-one (Carlsson and Törnqvist 2016); 4-hydroxybenzaldehyde (Degner et al. 2018); ethyl vinyl ketone (Carlsson et al. 2015); and cyclophosphamide (Gernaat et al. 2021).
Monien et al. used the method to detect the N-terminal adducts of glycidol (Hielscher et al. 2017) (the same adduct forms for fatty acid esters of glycidol (Abraham et al. 2019)), furfuryl alcohol (Sachse et al. 2017), and estragole and anethole that yield the same estragole adduct (Bergau et al. 2021). The available LOQs for some of these compounds are listed in Table 6. The structures of these valine adducts are listed in Table 3S.
Analytical methods based on enzymatic digestion of hemoglobin and subsequent measurement of the resulting N-terminal peptide adduct by LC−MS/MS have been described for acetaldehyde (Birt et al. 1998), 1,2:3,4-diepoxybutane (Basile et al. 2002; Kautiainen et al. 2000), isoprene diepoxide (Fred et al. 2005), and formaldehyde (Ospina et al. 2011; Yang et al. 2017). The work of Birt et al. (Birt et al. 1998) is an exemplary of a chemical approach to discover the structure of a stable adduct with chemicals. In vitro experiments with acetaldehyde and the corresponding peptides of the N-terminal of α- and β-chains were performed and the structure of the imidazoline was characterized by NMR and MS (corresponding to the product for formaldehyde, see Fig. 8). These methods provide an alternative approach for the quantitative analysis of N-terminal adducts, especially for adducts not reacting with the Edman reagents. At the CDC, the same approach was applied to measure N-terminal adducts with formaldehyde. After trypsin digestion of the hemoglobin adduct, a peptide with the formaldehyde conjugated to the N-terminal-valine formaldehyde-VHLTPEEK was quantified (Table 6, Fig. 8), by LC–MS/MS (CDC-NHANES 2020; Ospina et al. 2011; Yang et al. 2017). Using this method, formaldehyde-hemoglobin adduct levels among the US population were determined in 2013–2014 in non-smokers (n = 2149) (CDC-NHANES 2021c) and smokers (CDC-NHANES 2021a) (n = 132). Applying a similar method, the adduct of treosulfan was used to detect the N-terminal adduct 2,3,4‐trihydroxybutyl-VLSPADK of the reactive intermediate diepoxybutane. After enzymatic digestion, the 7-mer adducted peptide was analyzed by LC–MS/MS (Boysen et al. 2019). The same approach was used to analyze N-terminal N-acylated and deaminated Val. Such modifications hinder the modified Edman procedure. The authors tried different enzymes - trypsin, chymotrypsin, endoproteinase Glu-C (V8), and AspN - to search for N-terminal peptides of the α-chain of hemoglobin. Asp-N gave short peptides and good digestion yields of VLSPADK and VLSPA. Adducted VLSPA was used as target molecule of choice (Usuzawa et al. 2021). The maximum logD of VHLTPEEK, VLSPADK, and VLSPA are -9.71, -7.73, and -3.62. Therefore, the high logD of VLSPA indicates the best peptide fragment for N-terminal adduct analyses.
The Törnqvist group used the FITC-method to perform targeted and untargeted analyses (Carlsson et al. 2019, 2014; Carlsson and Törnqvist 2016). The LOQs for the synthesized putative adducts found in humans are excellent (Table 6). The same research group proposed the untargeted analysis of adducts with the N-terminal valines of hemoglobin (Carlsson et al. 2014). The identification of new adducts is proceeding very slowly, since the untargeted screening by MS analyses generates enormous and complex datasets that are both difficult and time-consuming to interpret (Carlsson et al. 2017, 2019; Carlsson and Törnqvist 2016, 2017). In contrast to the other omics research topics such as proteomics and metabolomics, there is no commercial software to evaluate adductomics data: programs such as the SALSA algorithm (Badghisi and Liebler 2002) were used for a short time.
Applications with the cysteine adducts
Cysteine adducts of arylamines formed after exposure to the arylamines or the corresponding nitroarenes was reviewed recently (Sabbioni 2017). The reactive intermediates are nitrosoarene compounds that react with β-Cys-93 of hemoglobin. The resultant sulfinamide adducts can be hydrolyzed under mild conditions (0.1 M NaOH or 0.1 M HCl at room temperature) and the released arylamines can be detected at very low levels after derivatization with fluorinated acid anhydrides. In animals given radiolabeled arylamines (Neumann et al. 1993), the hydrolyzable part is related to the presence of a sulfinamide. 4-Chloroaniline, nitrobenzene, N-acetylaniline, benzidine, and 3,3’-dichlorobenzidine gave adducts that were hydrolyzable, in yields of 93%, 95%, 84%, 88%, and 32%, respectively, in animals sacrificed after 24 h (Neumann et al. 1993). Hemoglobin modified in vitro with radiolabeled 4-aminobiphenyl yielded only hydrolyzable adducts (Green et al. 1984). In vitro reactions with erythrocytes and N-hydroxyaniline confirmed the presence of only sulfinamides (Moller et al. 2017). However, unpublished work generated by Wolfgang Albrecht, a PhD student of Prof. Neumann, Department of Pharmacology and Toxicology, Würzburg, showed that the fraction of hydrolyzable hemoglobin adducts formed in rats decreased with time (Albrecht 1985). The hydrolyzable fraction compared to the totally bound radioactivity decreased from 1 day versus 7 days postdosing: for benzidine from 88.3 to 58.8%, for nitrobenzene from 98 to 52.3%, and for acetanilide from 58.3 to 39.2%. We postulate that the presumed sulfinamides may have undergone oxidation to form the chemically more stable sulfonamide in vivo (or via an in vitro/ex vivo experimental artifact). Arylsulfonamides (Mosher et al. 1958) are more stable than arylsulfinamides towards the hydrolysis conditions (0.1 M HCl at room temperature) used by Albrecht.
Chemical hydrolysis of hemoglobin adducts of xenobiotics with cysteine has been used for years for the detection of hemoglobin adducts of arylamines (reviewed in (Sabbioni 2017)). The LOQs of such an approach is lower than of peptide adducts. Hemoglobin β-Cys-93 sulfinamide and sulfonamide adducts of 4-aminobiphenyl were identified as peptide adducts in mice (Table 6, Fig. 8) by orbitrap MS following the proteolysis of hemoglobin with trypsin, Glu-C endoproteinase, or Lys-C endoproteinase (Pathak et al. 2016). The obtained β-Cys-93 containing peptides have very low logD values (Table 5). This hinders a separation of the adducts from the rest of the protein digest. This technique is not sufficiently sensitive and cleavage of the adduct by acid hydrolysis must be applied to detect the released 4-aminobiphenyl for human biomonitoring (Cai et al. 2017).
A new, sensitive method using LC–MS/MS was published for the analysis of hemoglobin adducts of polycyclic aromatic amines deriving from nitro-polyaromatic hydrocarbons present in polluted air (Wheelock et al. 2018). A novel method for source-specific hemoglobin adducts of nitro-polycyclic aromatic hydrocarbons was also described (Vimercati et al. 2020). Extensive comparisons were made to early biological effects (Vimercati et al. 2020).
Adducts in addition to cysteine sulfinamides were found in rats given 1- and 2-naphthylamine (NA) S-(1-amino-2-naphthyl)cysteine and S-(4-amino-1-naphthyl)cysteine were respectively found in rats given 1-NA and in those given 2-NA (Linhart et al. 2021) (Fig. 8). The novel aminonaphthylcysteine adducts were formed via naphthylnitrenium ions and/or their metabolic precursors in the biotransformation of naphthylamines. The positive charge is delocalized over the molecule, and therefore as in this case, the electrophilic attack proceeded on a carbon. The carcinogenic isomer 2-NA formed adducts at 100-fold-higher levels than the non-carcinogenic 1-NA isomer. These adducts are an additional new tool to monitor exposure to arylamines. These naphthylnitrenium adducts are present at a much higher level than the sulfinamide adducts formed through the nitrosoarene metabolite. The level of sulfinamide adducts in hemoglobin does not depend only from the formation of N-hydroxyarylamine (Sabbioni 1994) but also from the capacity to form the nitrosoarene in the erythrocytes according to the Kiese cycle (Kiese 1974). Therefore, for example, the mutagenic and/or carcinogenic potency of monocyclic arylamines correlate inversely to the levels of hemoglobin adducts (Sabbioni and Sepai 1995). In contrast, the hemoglobin adduct levels found in rats of bicyclic and bifunctional arylamines such as 4,4’-methylenedianiline, 4,4’-methylenebis(2-chloroaniline), 4,4’-oxydianiline, 4,4’-thiodianiline, 3,3’-dichlorobenzidine and benzidine correlate with the carcinogenic potency (Sabbioni and Schutze 1998). Roughly, the mutagenic and carcinogenic potency of arylamines is associated to the relative stability of the nitrenium ion, but not necessarily to the hydrolyzable hemoglobin (sulfinamide) adduct levels (Sabbioni and Sepai 1995; Sabbioni and Wild 1992) (Fig. 1S). The best correlations are found by including only similar compounds in the assessment, e.g., monocyclic arylamines as one category. More parameters have to be included for an overall prediction of the mutagenic and carcinogenic properties of arylamines (Benigni 2005; Benigni et al. 2007). In summary, the adducts of the nitrenium ions or the nitrosoarene originate from the same critical metabolite, the N-hydroxyarylamine. The nitrenium ion adducts are more stable and are more adaptable to the analysis of intact peptide adducts than the hydrolyzable sulfinamide adducts.
Compounds other than arylamines form adducts with cysteine of hemoglobin. For example, benzene (Rappaport et al. 2005), styrene (Fustinoni et al. 1998) and naphthalene (Waidyanatha and Rappaport 2008). Estrogen quinone-derived reaction products with cysteine, including 17β-estradiol-2,3-quinone and 17β-estradiol-3,4-quinone, were found at higher levels in hemoglobin cancer patients than in controls (Lin et al. 2014).
Adducts other than with cysteine or the N-terminal valine were found in mice given 1-methoxy-3-indolylmethyl glucosinolate (Fig. 7). Adducts with the metabolically released isothiocyanate were found with histidine (Barknowitz et al. 2014). Hemoglobin adducts of phenylethyl-ITC, benzyl-ITC, and sulforaphane with lysine were found in one subject eating cruciferous vegetables such as water cress, garden cress and broccoli (Kumar and Sabbioni 2010). Nitration, chlorination, and oxidation products were found in hemoglobin of breast cancer patients (Chen et al. 2021). Pyrrolizidine adducts with cysteine and histidine were found in humans (Ma et al. 2021).
In toxicological investigations, mostly adducts with the N-terminal valine or with cysteine in the β-chain were investigated. Hemoglobin adducts were analyzed after acid or base treatment, which yields the parent compound or a metabolite that can be extracted and separated from the biological matrix. This enables good sensitivities of the assays.
Outlook
Many biomonitoring studies were performed using hemoglobin and albumin adducts in the last 40 years. Several compounds form adducts. With the progress of technology, researchers have wanted to take a global approach and have the vision to determine the individual exposome (Carlsson et al. 2019; Grigoryan et al. 2016). Methods are proposed to discover new chemicals on the adductome. The methods applied appear to be less sensitive than older methods (Table 3 and Table 6). Except for the large NHANES studies, most biomonitoring studies were performed with a small number of people. For analytical applications in forensic, food, drug, and clinical toxicology, accredited laboratories are performing the analyses with reference material. Therefore, in order for adduct research to progress, reference material should be used to make the analyses more reproducible. Several adducts are now commercially available. These are mostly adducts with single amino acids. To validate the analyses of adducts with larger peptides, the adducts should be synthesized and characterized, by at least 13C-NMR, 1H-NMR, UV, and MS. These synthetic peptide adducts along with the corresponding stable isotope labeled compounds should be used to evaluate the LOD and LOQs of the method. In addition, the sensitivity of the assay with larger peptides should be compared to the sensitivity of the assay with the classical assay after cleavage of the bond with the protein or after the digestion to the single amino acids. It might be worthwhile to compare the T3 peptide adduct analysis performance to the performance of the CPF adducts. Round robins should be organized to see if other laboratories measure comparable values. The detection limits of the synthetic compounds will show if the method is good enough to detect adducts in humans from environmental exposures.
Usually < 1% (Sabbioni and Turesky 2017) of the dose of potential adduct-forming compounds bind with albumin in vivo. The estimated exposure levels (Wambaugh et al. 2013, 2014) should be taken from work performed at EPA (https://comptox.epa.gov/dashboard). Using these predicted exposures, a daily dose can be estimated. Assuming an adduction level of < 1%, the daily albumin adduct level can be estimated from data obtained in animal experiments or from IVIVE predictions. If chronic exposure to the compound is likely and the adduct is stable, then the daily adduct level can be multiplied by 29. This yields the steady adduct level with albumin. If the detection limit of the assay performed with synthetic standards does not reach these levels, then it is highly unlikely to find adducts in environmentally exposed people.
To generate more preliminary data, the following road map is suggested. Instead of fishing in the dark, a more direct approach should be undertaken. Which compounds are important to include in biomonitoring studies? Databanks of potentially relevant compounds according to the lists published recently (Egeghy et al. 2016; Ring et al. 2019; Wang et al. 2020) should be used, a thorough prioritization of compounds should be undertaken, and the following values should be considered and introduced in the selection process: production volumes, toxicity, and predicted exposure levels (Blackburn et al. 2020; Dong et al. 2019; Sobus et al. 2019). From the selected list of compounds, the metabolism should be elucidated using experimental data, or predicted data from software such as QSAR Toolbox, Metaprint 2D, FAME, and Toxtree (Cronin et al. 2019; Kirchmair et al. 2015; Norinder et al. 2018; Shapiro et al. 2018; Suarez-Torres et al. 2020; Tan and Kirchmair 2014; Tian et al. 2018). In a next step, the structure of the potential adduct might be elucidated by the prediction of the reaction site by analogy and/or applying the concept of hard and soft nucleophiles, resp. electrophiles (LoPachin et al. 2012, 2019).
Practical skin sensitivity tests (OECD 2021a; OECD 2021b) are available. These are applied to reactions of chemicals to single amino acids or to small peptides with a free cysteine or lysine: a) the direct peptide reactivity assay, b) the amino acid derivative reactivity assay, and c) the kinetic direct peptide reactivity assay. The tests do not elucidate the structures of the reaction products, but only the disappearance of the original peptide after applying the chemical. Databanks of over 100 chemicals exist (Hoffmann et al. 2018; Urbisch et al. 2016, 2015). In addition, great efforts are put in prediction models for the assessment of new compounds especially for the cosmetic industry (Kimber 2021; Kleinstreuer et al. 2018; Natsch et al. 2020; Wareing et al. 2017). Synergies are possible between the researchers of laboratories interested in the development of methods to biomonitor people and to prevent release of skin sensitization products. Three compounds were tested recently to determine if skin sensitizing chemicals form albumin and hemoglobin adducts (Ndreu et al. 2020). It might be useful to introduce the short terminal peptides of the α- and ß-chain of hemoglobin, or the T3 peptide of albumin as probe for the reaction of potential sensitizing compounds.
For adduct analyses, presently the best sensitivity is reached with single amino acid adducts. Therefore, methods should be set up to aim at the amino acid hot spots discovered in vitro and confirmed partially in vivo. Some of these adducts are commercially available (Table 1S, 3S, 3, 6). Many compounds react with lysines. More compounds of significant potential environmental hazardous compounds should be added to the list of potential adduct-forming compounds. Starting with a diverse set of compounds, the targeted approach should be tested with pronase-digested albumin. Digestion of albumin to single amino acids yields for example lysine adducts (Kumar et al. 2009; Kumar and Sabbioni 2010; Sabbioni 1990; Sabbioni et al. 2012; Sabbioni and Wild 1991). This enables preliminary experiments to determine the sensitivity of the assay: LC–MS/MS, LC-HRMS and comparison to the predicted presence in the environment and the potential of adduct formation. In case of success, an untargeted approach might be tried to discover new compounds (e.g., lysine adducts) in samples collected from humans. The chemical properties of the potential adduct candidates should be predicted (logP, logD) with models to adjust the work up and conditions of the LC–MS/MS (preferably LC-HRMS) analyses. Untargeted MS analyses could be performed using the SAWTH-technique (Bruderer et al. 2018; Klont et al. 2020), neutral loss (LC–MS/MS (Barnaba et al. 2018; Dator et al. 2017)), and LC-HRMS (Carlsson et al. 2019). The newly discovered compounds identified by MS should be confirmed with synthetic standards. The same approach can be done with the other amino acid hot spots on hemoglobin and albumin.
Untargeted adductomics has not yielded new adducts that could be used in biomonitoring studies. The interpretation of the massive data appear to be too complicated (Carlsson et al. 2019). In addition, especially, for the analyses of albumin adducts, trypsin digestion yields large peptide fragments that cannot be analyzed with sufficient sensitivity (Preston et al. 2017). The method should be first tested with synthetic standards that have been characterized according to the standard protocols of organic chemistry.
Is untargeted adductomics feasible in the near future? The principle has potential as a tool to discover new markers of concern from both exposure and toxicological impact point of view. However, further improvements are necessary to make this approach fit-for-purpose with regard to human biomonitoring expectations, particularly for sensitivity (Hollender et al. 2017; Schymanski et al. 2015).
Alternative approaches to determine albumin and hemoglobin adducts are amino acid adducts of xenobiotics (valine, lysine) in urine (Mráz et al. 2020, 2016; Rabbani and Thornalley 2020), and mercapturic acids in urine (Bloch et al. 2019; Frigerio et al. 2019; Hanna and Anders 2020; Pluym et al. 2015; Wagner et al. 2006). However, like for most non-persistent chemicals, the urinary metabolites fluctuate substantially (LaKind et al. 2019; Pleil and Sobus 2013). For protein adducts, measurements have rarely been performed at different time points. Recently, Smith et al. (Smith et al. 2021) found a good intra class correlation coefficient (ICC = 0.91) for 14BQ adducts with albumin measured at 0, 56, and 84 days. For the other measured adducts without corresponding deuterated internal standard, the ICCs were below 0.62. However, for all products the adduct found in vivo was not confirmed and quantified with a synthetic standard. The low ICCs were justified with the varying air pollution measured as PM10, SO2 and NO2 concentrations during that period. The ICCs are used to show that the measurements give a reliable indication of the individual exposure. The following classifications are made for the reliability of the exposure measurements (LaKind et al. 2019): poor ICC < 0.4; fair to good ICC = 0.4 to < 0.75; and excellent for ICCs ≥ 0.75.
What are the future options of adductomics? The current tendency in molecular epidemiology is to collect data with the vision to be able to relate the exposome and other factors such as genetics and socioeconomic factors to disease (Vineis et al. 2020). However, the question arises as to how reliable and relevant the data are. Fishing into the data will lead to some potential relationships to one or more factors; however, how reproducible and significant are such exposure data? Working hypothesis should be built: what differences in adduct levels of a certain compound would lead to a disease? Perhaps using in vitro/in vivo relationships? Similar questions were raised and investigated in animal experiments. For example in aflatoxin research, it was of interest to determine the level of DNA adduct in the target organ relevant for liver tumor formation. Some relationship was found between species. The DNA chemical binding index of several chemicals was established in animals to evaluate a relationship between DNA binding level and likelihood of tumor formation (Lutz 1979; Otteneder and Lutz 1999). However, the vision of higher binding levels yielding more tumors could not be applied as a general model. In case–control studies with bladder cancer patients, significantly higher hemoglobin adduct levels were found (Skipper et al. 2003); however, the differences are so small that it is impossible to give a toxicological explanation. Originally, biomonitoring was developed to monitor workers. Most of the knowledge about exposure to chemicals in humans was discovered in workers. At the workplace, the occupational hygiene measures were improved, and the biomonitoring levels dropped for example in large German chemical companies such as Bayer with a great tradition in biomonitoring with scientists such as Miksche, Lewalter and now Leng. With compounds that are very toxic, such as aflatoxin, interventions were made, and the situation improved in many countries. Lead was reduced and the levels in children dropped. The levels diminished in the population.
How many chemicals of the > 400,000 are toxicologically relevant (Ring et al. 2019)? Is it possible to pick the dangerous candidates with biomonitoring studies, and if 1000 dangerous chemicals could be found, how significant are the health effects? And, if these chemicals are so dangerous, why were they not detected in the tests required to get them on the market? Would it not be easier to improve the OECD toxicological tests to avoid such compounds getting on the market? The chemicals on the market could be re-evaluated with new tests. In the outstanding EPIC studies (https://epic.iarc.fr/), a prospective study to link nutrition to cancer, numerous samples were collected, stored, and analyzed for many years. How clear and unambiguous are the results obtained from this study? What is more important—the poor nutrition, the socioeconomic factors, the environment, the lifestyle, the genes or just bad luck (Song et al. 2018; Tomasetti and Vogelstein 2015)?
Health data should be collected more thoroughly and included in geographical information systems. If some disease clusters are spotted, then it may be worthwhile to investigate more closely with biomonitoring studies. However, the difficulties of such approach might be hampered by the big ongoing globalization process. For example, often in Northern and Middle European countries, the hazardous work is performed by foreign workers. These workers go back to their home country and might get sick, and these cases are probably not recognized as occupational disease. In Switzerland, the cancer registries do not collect the information about the profession of the cases. Therefore, potential occupational links to the disease are missed.
Adductomic analyses are more work intensive and cost more than urinary analyses. Biomonitoring analyses cost at least 200 USD per sample and substance group (e.g., arylamines, http://www.ipasum.med.fau.de/files/2020/01/Preisliste.pdf) (Vorkamp and Knudsen 2019). Are the costs to monitor 100 classes of compounds and 100,000 people (= 2 × 107 USD for one spot sample) helping to improve public health? Is it worthwhile to do one spot samples especially for urinary analyses that vary substantially? In summary, biomonitoring and adductomics should be used on a carefully selected small number of people that are monitored through the years as sentinels for exposure to xenobiotics. A more complete evaluation of exposure will be more effective using computer models, wastewater, water, air, and food analyses.
References
Abraham K, Hielscher J, Kaufholz T, Mielke H, Lampen A, Monien B (2019) The hemoglobin adduct N-(2,3-dihydroxypropyl)-valine as biomarker of dietary exposure to glycidyl esters: a controlled exposure study in humans. Arch Toxicol 93(2):331–340. https://doi.org/10.1007/s00204-018-2373-y
Ahmed N, Dobler D, Dean M, Thornalley PJ (2005) Peptide mapping identifies hotspot site of modification in human serum albumin by methylglyoxal involved in ligand binding and esterase activity. J Biol Chem 280(7):5724–5732. https://doi.org/10.1074/jbc.M410973200
Albrecht W (1985) Untersuchungen zur Hämoglobinbindung aromatischer Amino- und Nitroverbindungen bei Ratten: Ein Beitrag zum Biomonitoring N-substituierter Arylverbindungen. PhD Thesis., Julius-Maximilians-Universität Würzburg
Aldini G, Gamberoni L, Orioli M et al (2006) Mass spectrometric characterization of covalent modification of human serum albumin by 4-hydroxy-trans-2-nonenal. J Mass Spectrom 41(9):1149–1161. https://doi.org/10.1002/jms.1067
Altomare A, Baron G, Balbinot M, et al. (2021) In-Depth AGE and ALE Profiling of Human Albumin in Heart Failure: Ex Vivo Studies. Antioxidants (Basel) 10(3) doi:https://doi.org/10.3390/antiox10030358
Andacht TM, Pantazides BG, Crow BS et al (2014) An enhanced throughput method for quantification of sulfur mustard adducts to human serum albumin via isotope dilution tandem mass spectrometry. J Anal Toxicol 38(1):8–15. https://doi.org/10.1093/jat/bkt088
Antunes AM, Godinho AL, Martins IL et al (2010) Protein adducts as prospective biomarkers of nevirapine toxicity. Chem Res Toxicol 23(11):1714–1725. https://doi.org/10.1021/tx100186t
Ariza A, Garzon D, Abanades DR et al (2012) Protein haptenation by amoxicillin: high resolution mass spectrometry analysis and identification of target proteins in serum. J Proteomics 77:504–520. https://doi.org/10.1016/j.jprot.2012.09.030
Bader M, Rosenberger W, Tsikas D, Gutzki FM (2013) N-(3-Chloro-2-hydroxypropyl)-valine in blood as haemoglobin adduct of epichlorohydrin [Biomonitoring Methods, 2013]. The MAK-Collection for Occupational Health and Safety. https://doi.org/10.1002/3527600418.bi10689e0013
Badghisi H, Liebler DC (2002) Sequence Mapping of Epoxide Adducts in Human Hemoglobin with LC-Tandem MS and the SALSA Algorithm. Chem Res Toxicol 15(6):799–805. https://doi.org/10.1021/tx015589+
Baillie TA (2020) Drug–protein adducts: past, present, and future. Med Chem Res 29(7):1093–1104. https://doi.org/10.1007/s00044-020-02567-8
Barknowitz G, Engst W, Schmidt S et al (2014) Identification and quantification of protein adducts formed by metabolites of 1-methoxy-3-indolylmethyl glucosinolate in vitro and in mouse models. Chem Res Toxicol 27(2):188–199. https://doi.org/10.1021/tx400277w
Barnaba C, Dellacassa E, Nicolini G, Nardin T, Serra M, Larcher R (2018) Non-targeted glycosidic profiling of international wines using neutral loss-high resolution mass spectrometry. J Chromatogr A 1557:75–89. https://doi.org/10.1016/j.chroma.2018.05.008
Basile A, Ferranti P, Pocsfalvi G et al (2001) A novel approach for identification and measurement of hemoglobin adducts with 1,2,3,4-diepoxybutane by liquid chromatography/electrospray ionisation mass spectrometry and matrix-assisted laser desorption/ionisation tandem mass spectrometry. Rapid Commun Mass Spectrom 15(8):527–540. https://doi.org/10.1002/rcm.263
Basile A, Ferranti P, Mamone G et al (2002) Structural analysis of styrene oxide/haemoglobin adducts by mass spectrometry: Identification of suitable biomarkers for human exposure evaluation. Rapid Commun Mass Spectrom 16(9):871–878. https://doi.org/10.1002/rcm.655
Bellamri M, Wang Y, Yonemori K et al (2018) Biomonitoring an albumin adduct of the cooked meat carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine in humans. Carcinogenesis 39(12):1455–1462. https://doi.org/10.1093/carcin/bgy125
Benigni R (2005) Structure-activity relationship studies of chemical mutagens and carcinogens: mechanistic investigations and prediction approaches. Chem Rev 105:1767–1800. https://doi.org/10.1021/cr030049y
Benigni R, Bossa C, Netzeva T, Rodomonte A, Tsakovska I (2007) Mechanistic QSAR of aromatic amines: new models for discriminating between homocyclic mutagens and nonmutagens, and validation of models for carcinogens. Environ Mol Mutagen 48(9):754–771. https://doi.org/10.1002/em.20355
Bergau N, Herfurth UM, Sachse B, Abraham K, Monien BH (2021) Bioactivation of estragole and anethole leads to common adducts in DNA and hemoglobin. Food Chem Toxicol 153:112253. https://doi.org/10.1016/j.fct.2021.112253
Birner G, Neumann HG (1988) Biomonitoring of aromatic amines II: Hemoglobin binding of some monocyclic aromatic amines. Arch Toxicol 62(2–3):110–115. https://doi.org/10.1007/BF00570128
Birt JEEC, Shuker DEG, Farmer PB (1998) Stable acetaldehyde-protein adducts as biomarkers of alcohol exposure. Chem Res Toxicol 11(2):136–142. https://doi.org/10.1021/tx970169z
Blackburn KL, Carr G, Rose JL, Selman BG (2020) An interim internal Threshold of Toxicologic Concern (iTTC) for chemicals in consumer products, with support from an automated assessment of ToxCastTM dose response data. Regul Toxicol Pharmacol 114:104656. https://doi.org/10.1016/j.yrtph.2020.104656
Bloch R, Schütze S-E, Müller E et al (2019) Non-targeted mercapturic acid screening in urine using LC-MS/MS with matrix effect compensation by postcolumn infusion of internal standard (PCI-IS). Anal Bioanal Chem 411(29):7771–7781. https://doi.org/10.1007/s00216-019-02166-6
Boysen G, Shimoni A, Danylesko I, Varda-Bloom N, Nagler A (2019) A simplified method for detection of N-terminal valine adducts in patients receiving treosulfan. Rapid Commun Mass Spectrom 33(21):1635–1642. https://doi.org/10.1002/rcm.8509
Breen M, Ring CL, Kreutz A, Goldsmith M-R, Wambaugh JF (2021) High-throughput PBTK models for in vitro to in vivo extrapolation. Expert Opin Drug Metab Toxicol 17(8):903–921. https://doi.org/10.1080/17425255.2021.1935867
Bruderer T, Varesio E, Hidasi AO et al (2018) Metabolomic spectral libraries for data-independent SWATH liquid chromatography mass spectrometry acquisition. Anal Bioanal Chem 410(7):1873–1884. https://doi.org/10.1007/s00216-018-0860-x
Cai T, Bellamri M, Ming X, Koh WP, Yu MC, Turesky RJ (2017) Quantification of hemoglobin and white blood cell DNA adducts of the tobacco carcinogens 2-amino-9H-pyrido[2,3-b]indole and 4-aminobiphenyl formed in humans by nanoflow liquid chromatography/ion trap multistage mass spectrometry. Chem Res Toxicol 30(6):1333–1343. https://doi.org/10.1021/acs.chemrestox.7b00072
Campos-Pinto I, Méndez L, Schouten J et al (2019) Epitope mapping and characterization of 4-hydroxy-2-nonenal modified-human serum albumin using two different polyclonal antibodies. Free Radic Biol Med 144:234–244. https://doi.org/10.1016/j.freeradbiomed.2019.05.008
Carlsson H, Törnqvist M (2016) Strategy for identifying unknown hemoglobin adducts using adductome LC-MS/MS data: Identification of adducts corresponding to acrylic acid, glyoxal, methylglyoxal, and 1-octen-3-one. Food Chem Toxicol 92:94–103. https://doi.org/10.1016/j.fct.2016.03.028
Carlsson H, Törnqvist M (2017) An adductomic approach to identify electrophiles in vivo. Basic Clin Pharmacol Toxicol 121(Suppl 3):44–54. https://doi.org/10.1111/bcpt.12715
Carlsson H, von Stedingk H, Nilsson U, Törnqvist M (2014) LC-MS/MS screening strategy for unknown adducts to N-terminal valine in hemoglobin applied to smokers and nonsmokers. Chem Res Toxicol 27(12):2062–2070. https://doi.org/10.1021/tx5002749
Carlsson H, Motwani HV, Osterman Golkar S, Törnqvist M (2015) Characterization of a hemoglobin adduct from ethyl vinyl ketone detected in human blood samples. Chem Res Toxicol 28(11):2120–2129. https://doi.org/10.1021/acs.chemrestox.5b00287
Carlsson H, Aasa J, Kotova N et al (2017) Adductomic Screening of Hemoglobin Adducts and Monitoring of Micronuclei in School-Age Children. Chem Res Toxicol 30(5):1157–1167. https://doi.org/10.1021/acs.chemrestox.6b00463
Carlsson H, Rappaport SM, Törnqvist M (2019) Protein adductomics: methodologies for untargeted screening of adducts to serum albumin and hemoglobin in human blood samples. High Throughput 8(1):6. https://doi.org/10.3390/ht8010006
CDC-NHANES (2019) N-terminal hemoglobin adducts of Acrylamide, Glycidamide, and Ethylene Oxide, Matrix: Red Blood Cells, https://wwwn.cdc.gov/nchs/data/nhanes/2015-2016/labmethods/AMDGYD_ETHOX_I_MET.pdf. Laboratory Methods 2015-2016
CDC-NHANES (2020) Laboratory Procedure Manual: Analyte: N-terminal hemoglobin adducts of Formaldehyde Matrix: Red Blood Cells. Method No: 1017. https://wwwn.cdc.gov/nchs/data/nhanes/2015-2016/labmethods/FORMAL_I_MET.pdf. Laboratory Methods 2015-2016
CDC-NHANES (2021a) Fourth National Report on Human Exposure to Environmental Chemicals Updated Tables, March 2021 Volume Four: NHANES 2011–2016, Hemoglobin adducts, formaldehyde, smokers, p29. https://www.cdc.gov/exposurereport/pdf/FourthReport_UpdatedTables_Volume4_Mar2021-508.pdf,
CDC-NHANES (2021b) NHANES Laboratory Data. https://wwwn.cdc.gov/nchs/nhanes/search/datapage.aspx?Component=Laboratory.
CDC-NHANES (2015–16) NHANES 2015–2016 Laboratory Methods, https://wwwn.cdc.gov/nchs/nhanes/search/datapage.aspx?Component=Laboratory&CycleBeginYear=2015.
CDC-NHANES (2021c) Fourth National Report on Human Exposure to Environmental Chemicals Updated Tables, March 2021 Volume Two: NHANES 2011–2016, Adducts of Hemoglobin, acrylamide, formaldehyde, and glycidamide, p26–28. https://www.cdc.gov/exposurereport/pdf/FourthReport_UpdatedTables_Volume2_Mar2021-508.pdf,
Chan CK, Chan KJ, Liu N, Chan W (2021) Quantitation of Protein Adducts of Aristolochic Acid I by Liquid Chromatography-Tandem Mass Spectrometry: A Novel Method for Biomonitoring Aristolochic Acid Exposure. Chem Res Toxicol 34(1):144–153. https://doi.org/10.1021/acs.chemrestox.0c00454
Charneira C, Grilo NM, Pereira SA et al (2012) N-terminal valine adduct from the anti-HIV drug abacavir in rat haemoglobin as evidence for abacavir metabolism to a reactive aldehyde in vivo. Br J Pharmacol 167(6):1353–1361. https://doi.org/10.1111/j.1476-5381.2012.02079.x
Charneira C, Nunes J, Antunes AMM (2020) 16alpha-Hydroxyestrone: Mass Spectrometry-Based Methodologies for the Identification of Covalent Adducts Formed with Blood Proteins. Chem Res Toxicol 33(8):2147–2156. https://doi.org/10.1021/acs.chemrestox.0c00171
Chen HJ, Chen YC (2012) Reactive nitrogen oxide species-induced post-translational modifications in human hemoglobin and the association with cigarette smoking. Anal Chem 84(18):7881–7890. https://doi.org/10.1021/ac301597r
Chen H-JC, Lin W-P, Chiu S-D, Fan C-H (2014) Multistage mass spectrometric analysis of human hemoglobin glutathionylation: correlation with cigarette smoking. Chem Res Toxicol 27(5):864–872. https://doi.org/10.1021/tx5000359
Chen DR, Hsieh WC, Liao YL, Lin KJ, Wang YF, Lin PH (2020) Imbalances in the disposition of estrogen and naphthalene in breast cancer patients: a potential biomarker of breast cancer risk. Sci Rep 10(1):11773. https://doi.org/10.1038/s41598-020-68814-5
Chen H-JC, Liao K-C, Tu C-W (2021) Quantitation of nitration, chlorination, and oxidation in hemoglobin of breast cancer patients by nanoflow liquid chromatography tandem mass spectrometry. Chem Res Toxicol 34(6):1664–1671. https://doi.org/10.1021/acs.chemrestox.1c00075
Chu S, Letcher RJ (2021) Identification and characterization of serum albumin covalent adduct formed with atrazine by liquid chromatography mass spectrometry. J Chromatogr B 1163:122503. https://doi.org/10.1016/j.jchromb.2020.122503
Chung MK, Grigoryan H, Iavarone AT, Rappaport SM (2014) Antibody enrichment and mass spectrometry of albumin-cys34 adducts. Chem Res Toxicol 27(3):400–407. https://doi.org/10.1021/tx400337k
Colombo G, Clerici M, Garavaglia ME et al (2016) A step-by-step protocol for assaying protein carbonylation in biological samples. J Chromatogr B 1019:178–190. https://doi.org/10.1016/j.jchromb.2015.11.052
Cronin MTD, Richarz A-N, Schultz TW (2019) Identification and description of the uncertainty, variability, bias and influence in quantitative structure-activity relationships (QSARs) for toxicity prediction. Regul Toxicol Pharmacol 106:90–104. https://doi.org/10.1016/j.yrtph.2019.04.007
Damsten MC, Commandeur JN, Fidder A et al (2007) Liquid chromatography/tandem mass spectrometry detection of covalent binding of acetaminophen to human serum albumin. Drug Metab Dispos 35(8):1408–1417. https://doi.org/10.1124/dmd.106.014233
Dator R, Carra A, Maertens L, Guidolin V, Villalta PW, Balbo S (2017) A high resolution/accurate mass (HRAM) data-dependent MS3 neutral loss screening, classification, and relative quantitation methodology for carbonyl compounds in saliva. J Am Soc Mass Spectrom 28(4):608–618. https://doi.org/10.1007/s13361-016-1521-y
Dawson DE, Ingle BL, Phillips KA, Nichols JW, Wambaugh JF, Tornero-Velez R (2021) Designing QSARs for Parameters of High-Throughput Toxicokinetic Models Using Open-Source Descriptors. Environ Sci Technol 55(9):6505–6517. https://doi.org/10.1021/acs.est.0c06117
Degner A, Carlsson H, Karlsson I et al (2018) Discovery of novel N-(4-Hydroxybenzyl)valine hemoglobin adducts in human blood. Chem Res Toxicol 31(12):1305–1314. https://doi.org/10.1021/acs.chemrestox.8b00173
Delatour T, Richoz J, Vouros P, Turesky RJ (2002) Simultaneous determination of 3-nitrotyrosine and tyrosine in plasma proteins of rats and assessment of artifactual tyrosine nitration. J Chromatogr B 779(2):189–199. https://doi.org/10.1016/S1570-0232(02)00370-7
Ding S-J, Carr J, Carlson JE et al (2008) Five tyrosines and two serines in human albumin are labeled by the organophosphorus agent FP-biotin. Chem Res Toxicol 21(9):1787–1794. https://doi.org/10.1021/tx800144z
Dong T, Zhang Y, Jia S et al (2019) Human indoor exposome of chemicals in dust and risk prioritization using EPA’s toxcast database. Environ Sci Technol 53(12):7045–7054. https://doi.org/10.1021/acs.est.9b00280
Egeghy PP, Sheldon LS, Isaacs KK et al (2016) Computational exposure science: an emerging discipline to support 21st-century risk assessment. Environ Health Perspect 124(6):697–702. https://doi.org/10.1289/ehp.1509748
Ehrenberg L, Hiesche KD, Osterman-Golkar S, Wenneberg I (1974) Evaluation of genetic risks of alkylating agents: tissue doses in the mouse from air contaminated with ethylene oxide. Mutat Res 24(2):83–103. https://doi.org/10.1016/0027-5107(74)90123-7
Ferranti P, Sannolo N, Mamone G et al (1996) Structural characterization by mass spectrometry of hemoglobin adducts formed after in vivo exposure to methyl bromide. Carcinogenesis 17(12):2661–2671. https://doi.org/10.1093/carcin/17.12.2661
Frank S, Renner T, Ruppert T, Scherer G (1998) Determination of albumin adducts of (+)-anti-benzo[a]pyrenediol epoxide using an high-performance liquid chromatographic column switching technique for sample preparation and gas chromatography-mass spectrometry for the final detection. J Chromatogr B 713(2):331–337. https://doi.org/10.1016/s0378-4347(98)00208-4
Fred C, Grawe J, Toernqvist M (2005) Hemoglobin adducts and micronuclei in rodents after treatment with isoprene monoxide or butadiene monoxide. Mutat Res, Genet Toxicol Environ Mutagen 585(1–2):21–32. https://doi.org/10.1016/j.mrgentox.2005.03.009
Frigerio G, Mercadante R, Polledri E, Missineo P, Campo L, Fustinoni S (2019) An LC-MS/MS method to profile urinary mercapturic acids, metabolites of electrophilic intermediates of occupational and environmental toxicants. J Chromatogr B 1117:66–76. https://doi.org/10.1016/j.jchromb.2019.04.015
Fu F, Sun F, Lu X et al (2019) A Novel Potential Biomarker on Y263 Site in Human Serum Albumin Poisoned by Six Nerve Agents. J Chromatogr B 1104:168–175. https://doi.org/10.1016/j.jchromb.2018.11.011
Fu F, Liu H, Gao R et al (2020) Protein adduct binding properties of tabun-subtype nerve agents after exposure in vitro and in vivo. Toxicol Lett 321:1–11. https://doi.org/10.1016/j.toxlet.2019.12.014
Fustinoni S, Colosio C, Colombi A, Lastrucci L, Yeowell-O’Connell K, Rappaport SM (1998) Albumin and hemoglobin adducts as biomarkers of exposure to styrene in fiberglass-reinforced-plastics workers. Int Arch Occup Environ Health 71(1):35–41. https://doi.org/10.1007/s004200050247
Gernaat SAM, von Stedingk H, Hassan M et al (2021) Cyclophosphamide exposure assessed with the biomarker phosphoramide mustard-hemoglobin in breast cancer patients: The Tailor Dose I study. Sci Rep 11(1):2707. https://doi.org/10.1038/s41598-021-81662-1
Golime R, Chandra B, Palit M, Dubey DK (2019) Adductomics: a promising tool for the verification of chemical warfare agents’ exposures in biological samples. Arch Toxicol 93(6):1473–1484. https://doi.org/10.1007/s00204-019-02435-4
Goto T, Murata K, Lee SH, Oe T (2013) Complete amino acid sequencing and immunoaffinity clean-up can facilitate screening of various chemical modifications on human serum albumin. Anal Bioanal Chem 405(23):7383–7395. https://doi.org/10.1007/s00216-013-7146-0
Green LC, Skipper PL, Turesky RJ, Bryant MS, Tannenbaum SR (1984) In vivo dosimetry of 4-aminobiphenyl in rats via a cysteine adduct in hemoglobin. Cancer Res 44(10):4254–4259
Gries W, Leng G (2013) Analytical determination of specific 4,4’-methylene diphenyl diisocyanate hemoglobin adducts in human blood. Anal Bioanal Chem 405(23):7205–7213. https://doi.org/10.1007/s00216-013-7171-z
Grigoryan H, Edmands WMB, Lu SS et al (2016) Adductomics pipeline for untargeted analysis of modifications to Cys34 of human serum albumin. Anal Chem 88:10504–10512. https://doi.org/10.1021/acs.analchem.6b02553
Groopman JD, Kensler TW, Wild CP (2008) Protective interventions to prevent aflatoxin-induced carcinogenesis in developing countries. Annu Rev Public Health 29:187–203. https://doi.org/10.1146/annurev.publhealth.29.020907.090859
Guengerich FP, Arneson KO, Williams KM, Deng Z, Harris TM (2002) Reaction of aflatoxin B(1) oxidation products with lysine. Chem Res Toxicol 15(6):780–792. https://doi.org/10.1021/tx010156s
Hallez F, Combès A, Desoubries C, Bossée A, Pichon V (2021) Development of a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the analysis of tryptic digest of human hemoglobin exposed to sulfur mustard. J Chromatogr B 1163:122518. https://doi.org/10.1016/j.jchromb.2020.122518
Hanna PE, Anders MW (2020) The mercapturic acid pathway. Crit Rev Tox. https://doi.org/10.1080/10408444.2019.1692191
Hettick JM, Siegel PD (2011) Determination of the toluene diisocyanate binding sites on human serum albumin by tandem mass spectrometry. Anal Biochem 414:232–238. https://doi.org/10.1016/j.ab.2011.03.035
Hettick JM, Siegel PD (2012) Comparative analysis of aromatic diisocyanate conjugation to human albumin utilizing multiplexed tandem mass spectrometry. Int J Mass Spectrom 309:168–175. https://doi.org/10.1016/j.ijms.2011.09.015
Hielscher J, Monien BH, Abraham K, Jessel S, Seidel A, Lampen A (2017) An isotope-dilution UPLC-MS/MS technique for the human biomonitoring of the internal exposure to glycidol via a valine adduct at the N-terminus of hemoglobin. J Chromatogr B 1059:7–13. https://doi.org/10.1016/j.jchromb.2017.05.022
Hoffmann S, Kleinstreuer N, Alépée N et al (2018) Non-animal methods to predict skin sensitization (I): the Cosmetics Europe database. Crit Rev Tox 48(5):344–358. https://doi.org/10.1080/10408444.2018.1429385
Hollender J, Schymanski EL, Singer HP, Ferguson PL (2017) Nontarget screening with High Resolution Mass Spectrometry in the environment: ready to go? Environ Sci Technol 51(20):11505–11512. https://doi.org/10.1021/acs.est.7b02184
Honda GS, Pearce RG, Pham LL et al (2019) Using the concordance of in vitro and in vivo data to evaluate extrapolation assumptions. PLoS ONE 14(5):e0217564. https://doi.org/10.1371/journal.pone.0217564
Ishii T, Ito S, Kumazawa S et al (2008) Site-specific modification of positively-charged surfaces on human serum albumin by malondialdehyde. Biochem Biophys Res Commun 371(1):28–32. https://doi.org/10.1016/j.bbrc.2008.03.140
John H, Siegert M, Gandor F et al (2016) Optimized verification method for detection of an albumin-sulfur mustard adduct at Cys(34) using a hybrid quadrupole time-of-flight tandem mass spectrometer after direct plasma proteolysis. Toxicol Lett 244:103–111. https://doi.org/10.1016/j.toxlet.2015.09.027
Käfferlein HU, Angerer J, Leng G, Gries W, Hartwig A, Commission MAK (2016) 3-Methyl-5-isopropylhydantoin as hemoglobin adduct of N,N-dimethylformamide and methylisocyanate [Biomonitoring Methods, 2015]. The MAK‐Collection for Occupational Health and Safety:554–577. https://doi.org/10.1002/3527600418.bi6812e2115a
Kautiainen A, Fred C, Rydberg P, Törnqvist M (2000) A liquid chromatography tandem mass spectrometric method for in vivo dose monitoring of diepoxybutane, a metabolite of butadiene. Rapid Commun Mass Spectrom 14(19):1848–1853. https://doi.org/10.1002/1097-0231(20001015)14:19%3c1848::AID-RCM106%3e3.0.CO
Kensler TW, Roebuck BD, Wogan GN, Groopman JD (2011) Aflatoxin: a 50-year odyssey of mechanistic and translational toxicology. Toxicol Sci 120(Suppl 1):S28-48. https://doi.org/10.1093/toxsci/kfq283
Kiese M (1974) Methemoglobinemia: A comprehensive treatise. CRC Press, Inc., Cleveland, OH. p 1–258, chemical abstracts accession number: 1976:431437
Kimber I (2021) The activity of methacrylate esters in skin sensitisation test methods II. A review of complementary and additional analyses. Regul Toxicol Pharmacol. https://doi.org/10.1016/j.yrtph.2020.104821
Kirchmair J, Goller AH, Lang D et al (2015) Predicting drug metabolism: experiment and/or computation? Nat Rev Drug Discov 14(6):387–404. https://doi.org/10.1038/nrd4581
Kleinstreuer NC, Hoffmann S, Alépée N et al (2018) Non-animal methods to predict skin sensitization (II): an assessment of defined approaches. Crit Rev Tox. https://doi.org/10.1080/10408444.2018.1429386
Klont F, Jahn S, Grivet C, König S, Bonner R, Hopfgartner G (2020) SWATH data independent acquisition mass spectrometry for screening of xenobiotics in biological fluids: Opportunities and challenges for data processing. Talanta 211:120747. https://doi.org/10.1016/j.talanta.2020.120747
Kojima K, Lee SH, Oe T (2016) An LC/ESI-SRM/MS method to screen chemically modified hemoglobin: simultaneous analysis for oxidized, nitrated, lipidated, and glycated sites. Anal Bioanal Chem 408(19):5379–5392. https://doi.org/10.1007/s00216-016-9635-4
Kranawetvogl A, Küppers J, Siegert M et al (2018) Bioanalytical verification of V-type nerve agent exposure: simultaneous detection of phosphonylated tyrosines and cysteine-containing disulfide-adducts derived from human albumin. Anal Bioanal Chem 410(5):1463–1474. https://doi.org/10.1007/s00216-017-0787-7
Kumar A, Sabbioni G (2010) New Biomarkers for Monitoring the Levels of Isothiocyanates in Humans. Chem Res Toxicol 23(4):756–765. https://doi.org/10.1021/tx900393t
Kumar A, Dongari N, Sabbioni G (2009) New isocyanate-specific albumin adducts of 4,4’-methylenediphenyl diisocyanate (MDI) in rats. Chem Res Toxicol 22(12):1975–1983. https://doi.org/10.1021/tx900270z
LaKind JS, Idri F, Naiman DQ, Verner MA (2019) Biomonitoring and Nonpersistent Chemicals-Understanding and Addressing Variability and Exposure Misclassification. Curr Environ Health Rep 6(1):16–21. https://doi.org/10.1007/s40572-019-0227-2
Leng G, Gries W (2014) Biomonitoring following a chemical incident with acrylonitrile and ethylene in 2008. Toxicol Lett 231(3):360–364. https://doi.org/10.1016/j.toxlet.2014.06.027
Lewalter J, Leng G, Ellrich D (2012) N-Benzylvaline after exposure to benzylchloride [Biomonitoring Methods, 2003]. The MAK-Collection for Occupational Health and Safety. https://doi.org/10.1002/3527600418.bi10044e0008
Li H, Grigoryan H, Funk WE et al (2011) Profiling Cys34 adducts of human serum albumin by fixed-step selected reaction monitoring. Mol Cell Proteomics 10(3):M110.004606. https://doi.org/10.1074/mcp.M110.004606
Li B, Eyer P, Eddleston M, Jiang W, Schopfer LM, Lockridge O (2013) Protein tyrosine adduct in humans self-poisoned by chlorpyrifos. Toxicol Appl Pharmacol 269(3):215–225. https://doi.org/10.1016/j.taap.2013.03.021
Lin C, Hsieh WC, Chen DR et al (2014) Hemoglobin adducts as biomarkers of estrogen homeostasis: elevation of estrogenquinones as a risk factor for developing breast cancer in Taiwanese women. Toxicol Lett 225(3):386–391. https://doi.org/10.1016/j.toxlet.2014.01.004
Lindh CH, Kristiansson MH, Berg-Andersson UA, Cohen AS (2005) Characterization of adducts formed between human serum albumin and the butadiene metabolite epoxybutanediol. Rapid Commun Mass Spectrom 19(18):2488–2496. https://doi.org/10.1002/rcm.2086
Lindstrom AB, Yeowell-O’Connell K, Waidyanatha S, McDonald TA, Golding BT, Rappaport SM (1998) Formation of hemoglobin and albumin adducts of benzene oxide in mouse, rat, and human blood. Chem Res Toxicol 11(4):302–310. https://doi.org/10.1021/tx9701788
Linhart I, Hanzlikova I, Mráz J, Duskova S, Tvrdikova M, Vachova H (2021) Novel aminoarylcysteine adducts in globin of rats dosed with naphthylamine and nitronaphthalene isomers. Arch Toxicol 95(1):79–89. https://doi.org/10.1007/s00204-020-02907-y
Liu C, Liang L, Xiang Y et al (2015) An improved method for retrospective quantification of sulfur mustard exposure by detection of its albumin adduct using ultra-high pressure liquid chromatography-tandem mass spectrometry. Anal Bioanal Chem 407(23):7037–7046. https://doi.org/10.1007/s00216-015-8842-8
Liyasova MS, Schopfer LM, Lockridge O (2012) Cresyl saligenin phosphate, an organophosphorus toxicant, makes covalent adducts with histidine, lysine, and tyrosine residues of human serum albumin. Chem Res Toxicol 25(8):1752–1761. https://doi.org/10.1021/tx300215g
LoPachin RM, Gavin T, DeCaprio A, Barber DS (2012) Application of the Hard and Soft, Acids and Bases (HSAB) Theory to Toxicant-Target Interactions. Chem Res Toxicol 25(2):239–251. https://doi.org/10.1021/tx2003257
LoPachin RM, Geohagen BC, Nordstroem LU (2019) Mechanisms of soft and hard electrophile toxicities. Toxicology 418:62–69. https://doi.org/10.1016/j.tox.2019.02.005
Luna LG, Green BJ, Zhang F, Arnold SM, Siegel PD, Bartels MJ (2014) Quantitation of 4,4’-methylene diphenyl diisocyanate human serum albumin adducts. Toxicol Rep 1:743–751. https://doi.org/10.1016/j.toxrep.2014.09.009
Lutz WK (1979) In vivo covalent binding of organic chemicals to DNA as a quantitative indicator in the process of chemical carcinogenesis. Mutat Res 65(4):289–356. https://doi.org/10.1016/0165-1110(79)90006-x
Ma J, Ruan J, Chen X et al (2019) Pyrrole-hemoglobin adducts, a more feasible potential biomarker of pyrrolizidine alkaloid exposure. Chem Res Toxicol 32(6):1027–1039. https://doi.org/10.1021/acs.chemrestox.8b00369
Ma J, Zhang W, He Y et al (2021) Clinical application of pyrrole-hemoglobin adducts as a biomarker of pyrrolizidine alkaloid exposure in humans. Arch Toxicol 95(2):759–765. https://doi.org/10.1007/s00204-020-02947-4
McCoy LF, Scholl PF, Sutcliffe AE et al (2008) Human aflatoxin albumin adducts quantitatively compared by ELISA, HPLC with fluorescence detection, and HPLC with isotope dilution mass spectrometry. Cancer Epidemiol Biomarkers Prev 17(7):1653–1657. https://doi.org/10.1158/1055-9965.epi-07-2780
McDonald TA, Waidyanatha S, Rappaport SM (1993) Measurement of adducts of benzoquinone with hemoglobin and albumin. Carcinogenesis 14(9):1927–1932. https://doi.org/10.1093/carcin/14.9.1927
Meng X, Howarth A, Earnshaw CJ et al (2013) Detection of drug bioactivation in vivo: mechanism of nevirapine-albumin conjugate formation in patients. Chem Res Toxicol 26(4):575–583. https://doi.org/10.1021/tx4000107
Mhike M, Chipinda I, Hettick JM et al (2013) Characterization of methylene diphenyl diisocyanate-haptenated human serum albumin and hemoglobin. Anal Biochem 440(2):197–204. https://doi.org/10.1016/j.ab.2013.05.022
Mhike M, Hettick JM, Chipinda I et al (2016) Characterization and comparative analysis of 2,4-toluene diisocyanate and 1,6-hexamethylene diisocyanate haptenated human serum albumin and hemoglobin. J Immunol Methods 431:38–44. https://doi.org/10.1016/j.jim.2016.02.005
Moller C, Davis WC, Thompson VR, Mari F, DeCaprio AP (2017) Proteomic analysis of thiol modifications and assessment of structural changes in hemoglobin induced by the aniline metabolites N-Phenylhydroxylamine and Nitrosobenzene. Sci Rep 7(1):14794. https://doi.org/10.1038/s41598-017-14653-w
Mosher CW, Silverstein RM, Crews OP Jr, Baker BR (1958) Potential anticancer agents. VI. Synthesis of α-amino-γ-sulfamoylbutyric acids with substituents on the sulfonamido nitrogen. J Org Chem 23:1257–1261. https://doi.org/10.1021/jo01103a005
Mráz J, Cimlová J, Stránský V, Nohová H, Kičová R, Šimek P (2006) N-Methylcarbamoyl-lysine adduct in globin: A new metabolic product and potential biomarker of N. N-Dimethylformamide in Humans Toxicol Lett 162(2):211–218. https://doi.org/10.1016/j.toxlet.2005.09.039
Mráz J, Hanzlikova I, Moulisova A et al (2016) Hydrolytic Cleavage products of globin adducts in urine as possible biomarkers of cumulative dose: proof of concept using styrene oxide as a model adduct-forming compound. Chem Res Toxicol 29(4):676–686. https://doi.org/10.1021/acs.chemrestox.5b00518
Mráz J, Hanzlikova I, Duskova S et al (2018) Determination of N-(2-hydroxyethyl)valine in globin of ethylene oxide-exposed workers using total acidic hydrolysis and HPLC-ESI-MS2. Toxicol Lett 298:76–80. https://doi.org/10.1016/j.toxlet.2018.06.1212
Mráz J, Hanzlikova I, Duskova S, Tvrdikova M, Linhart I (2020) N-(2-Hydroxyethyl)-l-valyl-l-leucine: a novel urinary biomarker of ethylene oxide exposure in humans. Toxicol Lett 326:18–22. https://doi.org/10.1016/j.toxlet.2020.03.004
Müller M (2013) N-(2,3-Dihydroxypropyl)-valine in blood as haemoglobin adduct of glycidol [Biomonitoring Methods, 2013]. The MAK-Collection for Occupational Health and Safety. https://doi.org/10.1002/3527600418.bi55652e0013
Natsch A, Haupt T, Wareing B, Landsiedel R, Kolle SN (2020) Predictivity of the kinetic direct peptide reactivity assay (kDPRA) for sensitizer potency assessment and GHS subclassification. Altex 37(4):652–664. https://doi.org/10.14573/altex.2004292
Ndreu L, Erber LN, Törnqvist M, Tretyakova NY, Karlsson I (2020) Characterizing adduct formation of electrophilic skin allergens with human serum albumin and hemoglobin. Chem Res Toxicol 33(10):2623–2636. https://doi.org/10.1021/acs.chemrestox.0c00271
Neumann HG, Birner G, Kowallik P, Schutze D, Zwirner-Baier I (1993) Hemoglobin adducts of N-substituted aryl compounds in exposure control and risk assessment. Environ Health Perspect 99:65–69. https://doi.org/10.1289/ehp.939965
Nieschalke K (2021) Proteinaddukte und Urinmetaboliten des Nagetierkanzerogens Methyleugenol als Biomarker der Exposition. PhD Thesis,. University of Potsdam
Noort D, Hulst AG, De Jong LPA, Benschop HP (1999) Alkylation of human serum albumin by sulfur mustard in vitro and in vivo: mass spectrometric analysis of a cysteine adduct as a sensitive biomarker of exposure. Chem Res Toxicol 12(8):715–721. https://doi.org/10.1021/tx9900369
Noort D, Fidder A, Hulst AG, de Jong LP, Benschop HP (2000) Diagnosis and dosimetry of exposure to sulfur mustard: development of a standard operating procedure for mass spectrometric analysis of haemoglobin adducts: exploratory research on albumin and keratin adducts. J Appl Toxicol 20(Suppl 1):S187–S192. https://doi.org/10.1002/1099-1263(200012)20:1+%3c::aid-jat676%3e3.0.co;2-f
Norinder U, Ahlberg E, Carlsson L (2018) Predicting ames mutagenicity using conformal prediction in the Ames/QSAR international challenge project. Mutagenesis 34(1):33–40. https://doi.org/10.1093/mutage/gey038
OECD (2021a) Guideline No. 497: Defined Approaches on Skin Sensitisation. OECD Guideline for Testing of Chemicals. doi:https://doi.org/10.1787/b92879a4-en
OECD (2021b) Test No. 442C: In Chemico Skin Sensitisation. OECD Guideline for Testing of Chemicals. doi:https://doi.org/10.1787/9789264229709-en
Olsen J, Bjørnsdottir I, Tjørnelund J, Honoré Hansen S (2003) Identification of the amino acids of human serum albumin involved in the reaction with the naproxen acyl coenzyme A thioester using liquid chromatography combined with fluorescence and mass spectrometric detection. Anal Biochem 312(2):148–156. https://doi.org/10.1016/S0003-2697(02)00462-1
Ospina M, Costin A, Barry AK, Vesper HW (2011) Characterization of N-terminal formaldehyde adducts to hemoglobin. Rapid Commun Mass Spectrom 25(8):1043–1050. https://doi.org/10.1002/rcm.4954
Osterman-Golkar S, Ehrenberg L, Segerback D, Hallstrom I (1976) Evaluation of genetic risks of alkylating agents. II. Haemoglobin as a dose monitor. Mutat Res 34(1):1–10. https://doi.org/10.1016/0027-5107(76)90256-6
Otteneder M, Lutz WK (1999) Correlation of DNA adduct levels with tumor incidence: carcinogenic potency of DNA adducts. Mutat Res 424(1–2):237–247. https://doi.org/10.1016/s0027-5107(99)00022-6
Padros J, Pelletier E (2001) Subpicogram determination of (+)-anti-benzo[a]pyrene diol-epoxide adducts in fish albumin and globin by high-performance liquid chromatography with fluorescence detection. Anal Chim Acta 426(1):71–77. https://doi.org/10.1016/S0003-2670(00)01173-9
Pahler A, Volkel W, Dekant W (1999) Quantitation of N epsilon-(dichloroacetyl)-L-lysine in proteins after perchloroethene exposure by gas chromatography-mass spectrometry using chemical ionization and negative ion detection followingimmunoaffinity chromatography. J Chromatogr A 847(1–2):25–34. https://doi.org/10.1016/s0021-9673(99)00276-9
Pathak KV, Bellamri M, Wang Y, Langouet S, Turesky RJ (2015) 2-Amino-9H-pyrido[2,3-b]indole (AalphaC) adducts and thiol oxidation of serum albumin as potential biomarkers of tobacco smoke. J Biol Chem 290(26):16304–16318. https://doi.org/10.1074/jbc.M115.646539
Pathak KV, Chiu T-L, Amin EA, Turesky RJ (2016) Methemoglobin formation and characterization of hemoglobin adducts of carcinogenic aromatic amines and heterocyclic aromatic amines. Chem Res Toxicol 29(3):255–269. https://doi.org/10.1021/acs.chemrestox.5b00418
Peng L, Turesky RJ (2014) Optimizing proteolytic digestion conditions for the analysis of serum albumin adducts of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine, a potential human carcinogen formed in cooked meat. J Proteomics 103:267–278. https://doi.org/10.1016/j.jprot.2014.03.023
Pleil JD, Sobus JR (2013) Estimating lifetime risk from spot biomarker data and intraclass correlation coefficients (ICC). J Toxicol Environ Health A 76(12):747–766. https://doi.org/10.1080/15287394.2013.821394
Pluym N, Gilch G, Scherer G, Scherer M (2015) Analysis of 18 urinary mercapturic acids by two high-throughput multiplex-LC-MS/MS methods. Anal Bioanal Chem 407(18):5463–5476. https://doi.org/10.1007/s00216-015-8719-x
Preston GW, Phillips DH (2019) Protein adductomics: analytical developments and applications in human biomonitoring. Toxics 7(2):29. https://doi.org/10.3390/toxics7020029
Preston GW, Plusquin M, Sozeri O et al (2017) Refinement of a methodology for untargeted detection of serum albumin adducts in human populations. Chem Res Toxicol 30(12):2120–2129. https://doi.org/10.1021/acs.chemrestox.7b00186
Preston GW, Dagnino S, Ponzi E et al (2020) Relationships between airborne pollutants, serum albumin adducts and short-term health outcomes in an experimental crossover study. Chemosphere 239:124667. https://doi.org/10.1016/j.chemosphere.2019.124667
Qiu Y, Burlingame AL, Benet LZ (1998) Mechanisms for covalent binding of benoxaprofen glucuronide to human serum albumin. Studies by tandem mass spectrometry. Drug Metab Dispos 26(3):246–256
Rabbani N, Thornalley PJ (2020) Reading patterns of proteome damage by glycation, oxidation and nitration: quantitation by stable isotopic dilution analysis LC-MS/MS. Essays Biochem 64(1):169–183. https://doi.org/10.1042/ebc20190047
Rajczewski AT, Ndreu L, Pujari SS et al (2021) Novel 4-hydroxybenzyl adducts in human hemoglobin: structures and mechanisms of formation. Chem Res Toxicol 34(7):1769–1781. https://doi.org/10.1021/acs.chemrestox.1c00111
Rappaport SM, Waidyanatha S, Yeowell-O’Connell K et al (2005) Protein adducts as biomarkers of human benzene metabolism. Chem- Biol Interact 153–154:103–109. https://doi.org/10.1016/j.cbi.2005.03.014
Regazzoni L, Del Vecchio L, Altomare A et al (2013) Human serum albumin cysteinylation is increased in end stage renal disease patients and reduced by hemodialysis: mass spectrometry studies. Free Radic Res 47(3):172–180. https://doi.org/10.3109/10715762.2012.756139
Regazzoni LG, Grigoryan H, Ji Z et al (2017) Using lysine adducts of human serum albumin to investigate the disposition of exogenous formaldehyde in human blood. Toxicol Lett 268:26–35. https://doi.org/10.1016/j.toxlet.2017.01.002
Ring CL, Arnot JA, Bennett DH et al (2019) Consensus modeling of median chemical intake for the U.S. population based on predictions of exposure pathways. Environ Sci Technol 53(2):719–732. https://doi.org/10.1021/acs.est.8b04056
Rubino FM, Pitton M, Di Fabio D, Colombi A (2009) Toward an “omic” physiopathology of reactive chemicals: Thirty years of mass spectrometric study of the protein adducts with endogenous and xenobiotic compounds. Mass Spec Rev 28(5):725–784. https://doi.org/10.1002/mas.20207
Rydberg P, von Stedingk H, Magnér J, Björklund J (2009) LC/MS/MS analysis of N-terminal protein adducts with improved sensitivity: a comparison of selected edman isothiocyanate reagents. Int J Anal Chem 2009:153472. https://doi.org/10.1155/2009/153472
Rynoe M, Anttinen-Klemetti T, Vaaranrinta R, Veidebaum T, Farmer PB, Peltonen K (2003) S-phenylcysteine adduct concentration in serum albumin of countryside residents and factory workers in Estonia. Toxicol Environ Chem 85(4–6):243–252. https://doi.org/10.1080/02772240410001665544
Sabbioni G (1990) Chemical and physical properties of the major serum albumin adduct of aflatoxin B1 and their implications for the quantification in biological samples. Chem Biol Interact 75(1):1–15. https://doi.org/10.1016/0009-2797(90)90018-I
Sabbioni G (1994) Hemoglobin binding of arylamines and nitroarenes: molecular dosimetry and quantitative structure-activity relationships. Environ Health Perspect 102(Suppl 6):61–67. https://doi.org/10.1289/ehp.94102s661
Sabbioni G (2017) Hemoglobin adducts and urinary metabolites of arylamines and nitroarenes. Chem Res Toxicol 30(10):1733–1766. https://doi.org/10.1021/acs.chemrestox.7b00111
Sabbioni G, Jones CR (2002) Biomonitoring of arylamines and nitroarenes. Biomarkers 7(5):347–421. https://doi.org/10.1080/13547500210147253
Sabbioni G, Schutze D (1998) Hemoglobin binding of bicyclic aromatic amines. Chem Res Toxicol 11(5):471–483. https://doi.org/10.1021/tx9701642
Sabbioni G, Sepai O (1995) Comparison of hemoglobin binding, mutagenicity, and carcinogenicity of arylamines and nitroarenes. Chimia 49(10):374–380
Sabbioni G, Turesky RJ (2017) Biomonitoring human albumin adducts: the past, the present, and the future. Chem Res Toxicol 30(1):332–366. https://doi.org/10.1021/acs.chemrestox.6b00366
Sabbioni G, Wild CP (1991) Identification of an aflatoxin G1-serum albumin adduct and its relevance to the measurement of human exposure to aflatoxins. Carcinogenesis 12(1):97–103. https://doi.org/10.1093/carcin/12.1.97
Sabbioni G, Wild D (1992) Quantitative structure-activity relationships of mutagenic aromatic and heteroaromatic azides and amines. Carcinogenesis 13(4):709–713. https://doi.org/10.1093/carcin/13.4.709
Sabbioni G, Hartley R, Henschler D, Hollrigl-Rosta A, Koeber R, Schneider S (2000) Isocyanate-specific hemoglobin adduct in rats exposed to 4, 4’-methylenediphenyl diisocyanate. Chem Res Toxicol 13(2):82–89. https://doi.org/10.1021/tx990096e
Sabbioni G, Hartley R, Schneider S (2001) Synthesis of adducts with amino acids as potential dosimeters for the biomonitoring of humans exposed to toluenediisocyanate. Chem Res Toxicol 14(12):1573–83. https://doi.org/10.1021/tx010053+
Sabbioni G, Dongari N, Kumar A (2010) Determination of a new biomarker in subjects exposed to 4,4’-methylenediphenyl diisocyanate. Biomarkers 15(6):508–515. https://doi.org/10.3109/1354750X.2010.490880
Sabbioni G, Gu Q, Vanimireddy LR (2012) Determination of isocyanate specific albumin-adducts in workers exposed to toluene diisocyanates. Biomarkers 17(2):150–159. https://doi.org/10.3109/1354750x.2011.645166
Sabbioni G, Sepai O (1998) Determination of human exposure to aflatoxins. In: Sinha KK, Bhatnagar D (eds) Mycotoxins in Agriculture and Food Safety. Marcel Dekker, Inc., New York, p 183–226. Chemical Abstract accession number: 1998:539217
Sachse B, Hielscher J, Lampen A, Abraham K, Monien BH (2017) A hemoglobin adduct as a biomarker for the internal exposure to the rodent carcinogen furfuryl alcohol. Arch Toxicol 91(12):3843–3855. https://doi.org/10.1007/s00204-017-2005-y
Schettgen T, Müller J, Ferstl C et al (2016) Haemoglobin adducts of ethylene oxide (N-(2-hydroxyethyl)valine), propylene oxide (N-(2-hydroxypropyl)valine), acrylonitrile (N-(2-cyanoethyl)valine), acrylamide (N-(2-carbonamide ethyl)valine) and glycidamide (N-(2-hydroxy-2-carbonamide ethyl)valine) [Biomonitoring Methods, 2015]. The MAK-Collection for Occupational Health and Safety. https://doi.org/10.1002/3527600418.bi7521e2115
Schutze D, Sepai O, Lewalter J, Miksche L, Henschler D, Sabbioni G (1995) Biomonitoring of workers exposed to 4,4’-methylenedianiline or 4,4’-methylenediphenyl diisocyanate. Carcinogenesis 16(3):573–582. https://doi.org/10.1093/carcin/16.3.573
Schymanski EL, Singer HP, Slobodnik J et al (2015) Non-target screening with high-resolution mass spectrometry: critical review using a collaborative trial on water analysis. Anal Bioanal Chem 407(21):6237–6255. https://doi.org/10.1007/s00216-015-8681-7
Seitz M, Kilo S, Eckert E, Muller J, Drexler H, Goen T (2018) Validity of different biomonitoring parameters for the assessment of occupational exposure to N, N-dimethylformamide (DMF). Arch Toxicol 92(7):2183–2193. https://doi.org/10.1007/s00204-018-2219-7
Shapiro AJ, Antoni S, Guyton KZ et al (2018) Software Tools to Facilitate Systematic Review Used for Cancer Hazard Identification. Environ Health Perspect 126(10):104501. https://doi.org/10.1289/EHP4224
Shrivastava A, Gupta V (2011) Methods for the determination of limit of detection and limit of quantitation of the analytical methods. Chron Young Sci 2(1):21–25. https://doi.org/10.4103/2229-5186.79345
Skipper PL, Tannenbaum SR (1990) Protein adducts in the molecular dosimetry of chemical carcinogens. Carcinogenesis 11(4):507–518. https://doi.org/10.1093/carcin/11.4.507
Skipper PL, Obiedzinski MW, Tannenbaum SR, Miller DW, Mitchum RK, Kadlubar FF (1985) Identification of the major serum albumin adduct formed by 4-aminobiphenyl in vivo in rats. Cancer Res 45(10):5122–5127
Skipper PL, Tannenbaum SR, Ross RK, Yu MC (2003) Nonsmoking-related arylamine exposure and bladder cancer risk. Cancer Epidemiol Biomarkers Prev 12(6):503–507
Smith JW, O’Meally RN, Ng DK et al (2021) Biomonitoring of ambient outdoor air pollutant exposure in humans using targeted serum albumin adductomics. Chem Res Toxicol 34(4):1183–1196. https://doi.org/10.1021/acs.chemrestox.1c00055
Sobus JR, Grossman JN, Chao A et al (2019) Using prepared mixtures of ToxCast chemicals to evaluate non-targeted analysis (NTA) method performance. Anal Bioanal Chem 411(4):835–851. https://doi.org/10.1007/s00216-018-1526-4
Song M, Vogelstein B, Giovannucci EL, Willett WC, Tomasetti C (2018) Cancer prevention: Molecular and epidemiologic consensus. Science 361(6409):1317. https://doi.org/10.1126/science.aau3830
Stepan AF, Walker DP, Bauman J et al (2011) Structural alert/reactive metabolite concept as applied in medicinal chemistry to mitigate the risk of idiosyncratic drug toxicity: a perspective based on the critical examination of trends in the top 200 drugs marketed in the United States. Chem Res Toxicol 24(9):1345–1410. https://doi.org/10.1021/tx200168d
Suarez-Torres JD, Ciangherotti CE, Jimenez-Orozco FA (2020) The predictivity of the -alert performance- functionality of the OECD QSAR-Toolbox (c/w further issues on the predictivity of nonclinical testing). Toxicol in Vitro 66:104858. https://doi.org/10.1016/j.tiv.2020.104858
Sun F, Ding J, Lu X et al (2017) Mass spectral characterization of tabun-labeled lysine biomarkers in albumin. J Chromatogr B 1057:54–61. https://doi.org/10.1016/j.jchromb.2017.04.047
Tailor A, Waddington JC, Meng X, Park BK (2016) Mass spectrometric and functional aspects of drug-protein conjugation. Chem Res Toxicol 29(12):1912–1935. https://doi.org/10.1021/acs.chemrestox.6b00147
Tan L, Kirchmair J (2014) Software for Metabolism Prediction Drug Metabolism Prediction. Wiley-VCH Verlag GmbH & Co. KGaA, p p27–52, doi:https://doi.org/10.1002/9783527673261.ch02
Tian S, Djoumbou-Feunang Y, Greiner R, Wishart DS (2018) CypReact: a software tool for in silico reactant prediction for human cytochrome P450 enzymes. J Chem Inf Model 58(6):1282–1291. https://doi.org/10.1021/acs.jcim.8b00035
Tomasetti C, Vogelstein B (2015) Cancer risk: role of environment-response. Science 347(6223):729–731. https://doi.org/10.1126/science.aaa6592
Törnqvist M, Mowrer J, Jensen S, Ehrenberg L (1986) Monitoring of environmental cancer initiators through hemoglobin adducts by a modified Edman degradation method. Anal Biochem 154(1):255–266. https://doi.org/10.1016/0003-2697(86)90524-5
Törnqvist M, Fred C, Haglund J, Helleberg H, Paulsson B, Rydberg P (2002) Protein adducts: quantitative and qualitative aspects of their formation, analysis and applications. J Chromatogr B 778(1–2):279–308. https://doi.org/10.1016/s1570-0232(02)00172-1
Urbisch D, Mehling A, Guth K et al (2015) Assessing skin sensitization hazard in mice and men using non-animal test methods. Regul Toxicol Pharmacol 71(2):337–351. https://doi.org/10.1016/j.yrtph.2014.12.008
Urbisch D, Becker M, Honarvar N et al (2016) Assessment of pre- and pro-haptens using nonanimal test methods for skin sensitization. Chem Res Toxicol 29(5):901–913. https://doi.org/10.1021/acs.chemrestox.6b00055
Usuzawa G, Lee SH, Oe T (2021) Alternative LC/ESI-MS/MS approach to screen hemoglobin N-terminal modifications. Int J Mass Spectrom 468:116651. https://doi.org/10.1016/j.ijms.2021.116651
van den Broek I, Sparidans RW, Schellens JHM, Beijnen JH (2007) Enzymatic digestion as a tool for the LC–MS/MS quantification of large peptides in biological matrices: Measurement of chymotryptic fragments from the HIV-1 fusion inhibitor enfuvirtide and its metabolite M-20 in human plasma. J Chromatogr B 854(1):245–259. https://doi.org/10.1016/j.jchromb.2007.04.026
van den Broek I, Niessen WM, van Dongen WD (2013) Bioanalytical LC-MS/MS of protein-based biopharmaceuticals. J Chromatogr B 929:161–179. https://doi.org/10.1016/j.jchromb.2013.04.030
van der Schans MJ, Hulst AG, van der Riet-van OD, Noort D, Benschop HP, Dishovsky C (2013) New tools in diagnosis and biomonitoring of intoxications with organophosphorothioates: case studies with chlorpyrifos and diazinon. Chem Biol Interact 203(1):96–102. https://doi.org/10.1016/j.cbi.2012.10.014
Van Nieuwenhuyse A, Fierens S, De Smedt T et al (2014) Acrylonitrile exposure assessment in the emergency responders of a major train accident in Belgium: a human biomonitoring study. Toxicol Lett 231(3):352–359. https://doi.org/10.1016/j.toxlet.2014.08.013
Vimercati L, Bisceglia L, Cavone D et al (2020) Environmental Monitoring of PAHs Exposure, Biomarkers and Vital Status in Coke Oven Workers. Int J Environ Res Public Health 17(7):2199. https://doi.org/10.3390/ijerph17072199
Vineis P, Robinson O, Chadeau-Hyam M, Dehghan A, Mudway I, Dagnino S (2020) What is new in the exposome? Environ Int 143:105887. https://doi.org/10.1016/j.envint.2020.105887
von der Wellen J, Winterhalter P, Siegert M, Eyer F, Thiermann H, John H (2018) A toolbox for microbore liquid chromatography tandem-high-resolution mass spectrometry analysis of albumin-adducts as novel biomarkers of organophosphorus pesticide poisoning. Toxicol Lett 292:46–54. https://doi.org/10.1016/j.toxlet.2018.04.025
von Stedingk H, Rydberg P, Törnqvist M (2010) A new modified Edman procedure for analysis of N-terminal valine adducts in hemoglobin by LC-MS/MS. J Chromatogr B 878(27):2483–2490. https://doi.org/10.1016/j.jchromb.2010.03.034
von Stedingk H, Vikstrom AC, Rydberg P et al (2011) Analysis of hemoglobin adducts from acrylamide, glycidamide, and ethylene oxide in paired mother/cord blood samples from Denmark. Chem Res Toxicol 24(11):1957–1965. https://doi.org/10.1021/tx200284u
von Stedingk H, Xie H, Hatschek T et al (2014) Validation of a novel procedure for quantification of the formation of phosphoramide mustard by individuals treated with cyclophosphamide. Cancer Chemother Pharmacol 74(3):549–558. https://doi.org/10.1007/s00280-014-2524-7
Vorkamp K, Knudsen BE (2019) Survey of tentative prices for biomarker analyses. Additional Deliverable Report AD 9.2 HORIZON2020 Programme, Contract No. 733032 HBM4EU, www.hbm4eu.eu/deliverables/.
Wagner S, Scholz K, Donegan M, Burton L, Wingate J, Völkel W (2006) Metabonomics and biomarker discovery: LC−MS metabolic profiling and constant neutral loss scanning combined with multivariate data analysis for mercapturic acid analysis. Anal Chem 78(4):1296–1305. https://doi.org/10.1021/ac051705s
Waidyanatha S, Rappaport SM (2008) Hemoglobin and albumin adducts of naphthalene-1,2-oxide, 1,2-naphthoquinone and 1,4-naphthoquinone in Swiss Webster mice. Chem Biol Interact 172(2):105–114. https://doi.org/10.1016/j.cbi.2008.01.004
Waidyanatha S, McDonald TA, Lin PH, Rappaport SM (1994) Measurement of hemoglobin and albumin adducts of tetrachlorobenzoquinone. Chem Res Toxicol 7(3):463–468
Waidyanatha S, Yeowell-O’Connell K, Rappaport SM (1998) A new assay for albumin and hemoglobin adducts of 1,2- and 1,4-benzoquinones. Chem Biol Interact 115(2):117–139. https://doi.org/10.1016/s0009-2797(98)00067-2
Walker JE (1976) Lysine residue 199 of human serum albumin is modified by acetylsalicylic acid. FEBS Lett 66(2):173–175. https://doi.org/10.1016/0014-5793(76)80496-6
Wambaugh JF, Setzer RW, Reif DM et al (2013) High-throughput models for exposure-based chemical prioritization in the ExpoCast project. Environ Sci Technol 47(15):8479–8488. https://doi.org/10.1021/es400482g
Wambaugh JF, Wang A, Dionisio KL et al (2014) High Throughput Heuristics for Prioritizing Human Exposure to Environmental Chemicals. Environ Sci Technol 48(21):12760–12767. https://doi.org/10.1021/es503583j
Wambaugh JF, Hughes MF, Ring CL et al (2018) Evaluating In Vitro-In Vivo Extrapolation of Toxicokinetics. Toxicol Sci 163(1):152–169. https://doi.org/10.1093/toxsci/kfy020
Wang Y, Peng L, Bellamri M, Langouet S, Turesky RJ (2015) Mass spectrometric characterization of human serum albumin adducts formed with N-oxidized metabolites of 2-amino-1-methylphenylimidazo[4,5-b]pyridine in human plasma and hepatocytes. Chem Res Toxicol 28(5):1045–1059. https://doi.org/10.1021/acs.chemrestox.5b00075
Wang Y, Villalta PW, Peng L et al (2017) Mass spectrometric characterization of an acid-labile adduct formed with 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine and albumin in humans. Chem Res Toxicol 30(2):705–714. https://doi.org/10.1021/acs.chemrestox.6b00426
Wang Z, Walker GW, Muir DCG, Nagatani-Yoshida K (2020) Toward a global understanding of chemical pollution: a first comprehensive analysis of national and regional chemical inventories. Environ Sci Technol 54(5):2575–2584. https://doi.org/10.1021/acs.est.9b06379
Wareing B, Urbisch D, Kolle SN, et al. (2017) Prediction of skin sensitization potency sub-categories using peptide reactivity data. Toxicol In Vitro 45(Part_1):134–145. https://doi.org/10.1016/j.tiv.2017.08.015
Wheelock K, Zhang JJ, McConnell R et al (2018) A novel method for source-specific hemoglobin adducts of nitro-polycyclic aromatic hydrocarbons. Environ Sci Process Impacts 20(5):780–789. https://doi.org/10.1039/C7EM00522A
Wiesner-Reinhold M, Barknowitz G, Florian S et al (2019) 1-Methoxy-3-indolylmethyl DNA adducts in six tissues, and blood protein adducts, in mice under pak choi diet: time course and persistence. Arch Toxicol 93(6):1515–1527. https://doi.org/10.1007/s00204-019-02452-3
Wild CP, Garner RC, Montesano R, Tursi F (1986) Aflatoxin B1 binding to plasma albumin and liver DNA upon chronic administration to rats. Carcinogenesis 7(6):853–858. https://doi.org/10.1093/carcin/7.6.853
Williams NH, Harrison JM, Read RW, Black RM (2007) Phosphylated tyrosine in albumin as a biomarker of exposure to organophosphorus nerve agents. Arch Toxicol 81(9):627–639. https://doi.org/10.1007/s00204-007-0191-8
Witort E, Capaccioli S, Becatti M et al (2016) Albumin Cys34 adducted by acrolein as a marker of oxidative stress in ischemia-reperfusion injury during hepatectomy. Free Radic Res 50(8):831–839. https://doi.org/10.1080/10715762.2016.1179736
Wogan GN, Kensler TW, Groopman JD (2012) Present and future directions of translational research on aflatoxin and hepatocellular carcinoma. A review. Food Addit Contam Part A Chem Anal Control Expo Risk Assess 29(2):249–57. https://doi.org/10.1080/19440049.2011.563370
Wollin KM, Bader M, Muller M, Lilienblum W, Csicsaky M (2014) Assessment of long-term health risks after accidental exposure using haemoglobin adducts of epichlorohydrin. Toxicol Lett 231(3):378–386. https://doi.org/10.1016/j.toxlet.2014.07.020
Xiang W, Weisbach V, Sticht H et al (2013) Oxidative stress-induced posttranslational modifications of human hemoglobin in erythrocytes. Arch Biochem Biophys 529(1):34–44. https://doi.org/10.1016/j.abb.2012.11.002
Xu H, Nie Z, Zhang Y et al (2014) Four sulfur mustard exposure cases: Overall analysis of four types of biomarkers in clinical samples provides positive implication for early diagnosis and treatment monitoring. Toxicol Rep 1:533–543. https://doi.org/10.1016/j.toxrep.2014.07.017
Yamagishi Y, Iwase H, Ogra Y (2021) Effects of human serum albumin on post-mortem changes of malathion. Sci Rep 11(1):11573. https://doi.org/10.1038/s41598-021-91145-y
Yang M, Ospina M, Tse C, Toth S, Caudill SP, Vesper HW (2017) Ultraperformance Liquid Chromatography Tandem Mass Spectrometry Method To Determine Formaldehyde Hemoglobin Adducts in Humans as Biomarker for Formaldehyde Exposure. Chem Res Toxicol 30(8):1592–1598. https://doi.org/10.1021/acs.chemrestox.7b00114
Yang M, Frame T, Tse C, Vesper HW (2018) High-throughput, simultaneous quantitation of hemoglobin adducts of acrylamide, glycidamide, and ethylene oxide using UHPLC-MS/MS. J Chromatogr B 1086:197–205. https://doi.org/10.1016/j.jchromb.2018.03.048
Yano Y, Schiffman C, Grigoryan H et al (2020) Untargeted adductomics of newborn dried blood spots identifies modifications to human serum albumin associated with childhood leukemia. Leuk Res 88:106268. https://doi.org/10.1016/j.leukres.2019.106268
Yeo TH, Ho ML, Loke WK (2008) Development of a liquid chromatography-multiple reaction monitoring procedure for concurrent verification of exposure to different forms of mustard agents. J Anal Toxicol 32(1):51–56
Yvon M, Anglade P, Wal JM (1989) Binding of benzyl penicilloyl to human serum albumin. Evidence for a highly reactive region at the junction of domains 1 and 2 of the albumin molecule. FEBS Lett 247(2):273–278. https://doi.org/10.1016/0014-5793(89)81351-1
Yvon M, Anglade P, Wal JM (1990) Identification of the binding sites of benzyl penicilloyl, the allergenic metabolite of penicillin, on the serum albumin molecule. FEBS Lett 263(2):237–240. https://doi.org/10.1016/0014-5793(90)81382-x
Zia-Amirhosseini P, Ding A, Burlingame AL, McDonagh AF, Benet LZ (1995) Synthesis and mass-spectrometric characterization of human serum albumins modified by covalent binding of two non-steroidal anti-inflammatory drugs: tolmetin and zomepirac. Biochem J 311(Pt 2):431–435. https://doi.org/10.1042/bj3110431
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Sabbioni, G., Day, B.W. Quo vadis blood protein adductomics?. Arch Toxicol 96, 79–103 (2022). https://doi.org/10.1007/s00204-021-03165-2
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DOI: https://doi.org/10.1007/s00204-021-03165-2