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The text discusses the research on EVALI (electronic cigarettes or vaping product use-associated lung injury) and its impact on public health. It highlights the outbreak of EVALI in the United States, the toxicological aspects of vaping fluids, and the response of official bodies in Europe. The text also delves into toxicological research avenues, clinical manifestations of EVALI, and the urgent need for further experimental and clinical research on this issue. The complexity of EVALI necessitates ongoing research and contributions to the field of toxicology. [Extracted from the article]

The article discusses the trends in research on advanced glycation end products (AGEs), which are compounds formed between reducing sugars and proteins, lipids, or nucleic acids. Research has shown a link between endogenously produced AGEs and chronic diseases, leading to concerns about the potential health risks associated with dietary intake of AGEs. The article highlights the need for further studies to assess the health risks of dietary intake of AGEs, including properly designed human or animal studies. Additionally, research directions include studying AGE chemistry, receptors and signaling pathways, and the role of AGEs in chronic diseases, especially cancer. [Extracted from the article]

After sample enrichment, mass spectrometry may simultaneously identify ricin peptide fingerprints and in vitro RNA substrates that have been deadenylated by the ricin A-chain and would allow for quick and sensitive detection of biological active ricin. Reports in the lay press on intended terrorist attacks with ricin or castor seeds have reached recent publicity (Anonymous [3]; Noryskiewicz [15]), reminiscent of earlier cases in the United States (Audi et al [4]) and elsewhere (Abbes et al [1]). Assays have been developed, where ricin is enriched from samples using ricin-specific antibodies. According to recent evidence antibody cocktails consisting of chain A and chain B antibodies show better neutralizing activity at lower antibody doses compared to antibodies directed against only one chain (Rong et al [20], Orsini Delgado [17]). [Extracted from the article]

Recently, the cases of Sergei and Yulia Skripal and of Alexei Navalny have attracted considerable public interest in acetylcholine esterase inhibitors in general, and Novichok agents in particular. The name "Novichok" is given to chemical warfare agents supposedly developed in the former Soviet Union between the 1970s and the 1990s, as a reaction to the British/American invention of VX agent. These three newcomer agents were synthesized much like VX, tabun, soman, and sarin, as unitary agents, meaning that the chemical structure is altered during production so that maximum potency occurs rapidly at the outset. In response, development of binary newcomer agents escalated at GosNIIOKhT, and in 1989 the first known binary newcomer agent, Novichok-5 was synthesized off the base structure of A-232 i " (for detailed references, see Chai et al. [2]). [Extracted from the article]

The "totality" of the human exposure is conceived to encompass life-associated endogenous and exogenous aggregate exposures. Process-related contaminants (PRCs) are not only formed in foods by heat processing, but also occur endogenously in the organism as physiological components of energy metabolism, potentially also generated by the human microbiome. To arrive at a comprehensive risk assessment, it is necessary to understand the contribution of in vivo background occurrence as compared to the ingestion from exogenous sources. Hence, this review provides an overview of the knowledge on the contribution of endogenous exposure to the overall exposure to putative genotoxic food contaminants, namely ethanol, acetaldehyde, formaldehyde, acrylamide, acrolein, α,β-unsaturated alkenals, glycation compounds, N-nitroso compounds, ethylene oxide, furans, 2- and 3-MCPD, and glycidyl esters. The evidence discussed herein allows to conclude that endogenous formation of some contaminants appears to contribute substantially to the exposome. This is of critical importance for risk assessment in the cases where endogenous exposure is suspected to outweigh the exogenous one (e.g. formaldehyde and acrolein). [ABSTRACT FROM AUTHOR]

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Because of the high pKa of boric acid, inorganic borates, when taken up by the human or animal organism, exist in the body almost exclusively in the form of non-dissociated boric acid. Therefore, the variety of inorganic boron compounds is commonly addressed in the toxicological literature as "boron" (B). There is a discussion concerning categorisation of inorganic boron compounds as reproductive toxins. Boron treatment of rats, mice and dogs was dose-dependently associated with testicular toxicity, characterised by inhibited spermiation at lower dose levels and by reduction of epididymal sperm counts at higher dose levels. The NOAEL for such fertility effects of boric acid in male rats (oral feeding, Sprague Dawley strain) was evaluated to be 17.5 mg B/kg bw per day. As far as developmental toxicity is concerned, oral dosing of 9.6 mg B/kg bw daily to female pregnant Sprague Dawley rats remained without effects, with foetal skeletal effects observed at higher doses. Therefore, 9.6 mg B/kg bw (oral dosing) was evaluated as NOAEL for developmental effects of boric acid. The blood level in rats, equivalent to this NOAEL, is 1270 ng B/g. As far as B-exposed humans are concerned, field studies on the effect of boron on human reproduction are possible only in a few boron-rich geographical areas. Published field studies were conducted in China's Liaoning province, the Argentinian Andes and Western Anatolia/Turkey. Particularly relevant are studies on occupationally B-exposed groups, because the potential exposure to boron is much higher in occupational compared to environmental settings. Comparison of estimated daily B exposure levels in humans and actually measured B blood levels confirms the preference of biomonitoring for exposure assessment in environmental and occupational studies. A boron blood level scaling shows that the levels of high occupational B exposures reported in China and in Turkey are compatible. Compared to the experimental B blood levels at boron-related NOAELs for male fertility and for developmental toxicity in rats, the human blood level means of the highest occupational exposure groups in China and in Turkey are lower by factors of > 4 and > 2, respectively. Basically, concentrations of B within the body that exert reproductive toxicity in humans are not reached under the conditions of human normal handling and use, including conditions of extreme occupational exposures. In consequence, all relevant results of studies into human reproductive toxicity of B are basically negative. Considering the effective doses, there is no scientific contradiction between experimental and human results of B reproductive toxicity. [ABSTRACT FROM AUTHOR]

The results indicate that the cytotoxicity of CP-55940 towards RD cells (skeletal muscle cells) is mediated by the CB1 receptor, but not by the CB2 receptor. CB1 receptors are mainly expressed in the brain and modulate neurotransmitter signaling, whereas CB2 receptors are abundant in immune tissues (Luethi and Liechti [11]). These effects were attenuated by pre-incubation with AM251, a selective CB1 receptor antagonist, but not by pre-incubation with AM630, a selective CB2 receptor antagonist. Meyer ([13]) pointed out that synthetic cannabinoids with a high affinity and intrinsic activity at cannabinoid CB1 receptors exert stronger physiological and psychological effects than tetrahydrocannabinol (THC), which may be in line with their high potential to trigger psychotic-like symptoms. [Extracted from the article]

Boron-associated shifts in sex ratios at birth were suggested earlier and attributed to a decrease in Y- vs. X-bearing sperm cells. As the matter is pivotal in the discussion of reproductive toxicity of boron/borates, re-investigation in a highly borate-exposed population was required. In the present study, 304 male workers in Bandirma and Bigadic (Turkey) with different degrees of occupational and environmental exposure to boron were investigated. Boron was quantified in blood, urine and semen, and the persons were allocated to exposure groups along B blood levels. In the highest ("extreme") exposure group (n = 69), calculated mean daily boron exposures, semen boron and blood boron concentrations were 44.91 ± 18.32 mg B/day, 1643.23 ± 965.44 ng B/g semen and 553.83 ± 149.52 ng B/g blood, respectively. Overall, an association between boron exposure and Y:X sperm ratios in semen was not statistically significant (p > 0.05). Also, the mean Y:X sperm ratios in semen samples of workers allocated to the different exposure groups were statistically not different in pairwise comparisons (p > 0.05). Additionally, a boron-associated shift in sex ratio at birth towards female offspring was not visible. In essence, the present results do not support an association between boron exposure and decreased Y:X sperm ratio in males, even under extreme boron exposure conditions. [ABSTRACT FROM AUTHOR]

The PON1 Q192R genotype was measured by real-time polymerase chain reaction, and the serum Q and R isoenzyme activity levels were measured with PON1-specific substrates. Archives of Toxicology have a history of 70 years in publishing research reports on acetylcholine esterase inhibitors (Vogel [14]). QQ homozygous individuals produce only the Q isoenzyme, which effectively hydrolyzes nerve agents like sarin. [Extracted from the article]

Almost 6 years ago, a Guest Editorial of Archives of Toxicology was published by Henkler and Luch ([10]), pointing to toxicological problems associated with the use of e-cigarettes. Following earlier subchronic inhalation studies in rats on the main e-cigarette components propylene glycol, glycerin and nicotine (Phillips et al. [17]), subchronic inhalation toxicity studies of aerosols from flavoured e-liquids are being reported by Ho et al. ([11]). In view of a bone-preserving effect of e-vapour aerosols relative to cigarette smoke exposure, it was concluded that e-vapour products could potentially constitute less harmful alternatives to cigarettes in situations in which bone health is of importance. 10.2174/1574886313666180227110556 19 Reumann MK, Schaefer J, Titz B. E-vapor aerosols do not compromise bone integrity relative to cigarette smoke after 6-month inhalation in an ApoE-/- mouse model. [Extracted from the article]

Boric acid and sodium borates are currently classified in the EU-CLP regulation as “toxic to reproduction” under “Category 1B”, with hazard statement of H360FD. However, so far field studies on male reproduction in China and in Turkey could not confirm such boron-associated toxic effects. As validation by another independent study is still required, the present study has investigated possible boron-associated effects on male reproduction in workers (n = 212) under different boron exposure conditions. The mean daily boron exposure (DBE) and blood boron concentration of workers in the extreme exposure group (n = 98) were 47.17 ± 17.47 (7.95-106.8) mg B/day and 570.6 ± 160.1 (402.6-1100) ng B/g blood, respectively. Nevertheless, boron-associated adverse effects on semen parameters, as well as on FSH, LH and total testosterone levels were not seen, even within the extreme exposure group. With this study, a total body of evidence has accumulated that allows to conclude that male reproductive effects are not relevant to humans, under any feasible and realistic conditions of exposure to inorganic boron compounds. [ABSTRACT FROM AUTHOR]

Boric acid and sodium borates are currently classified as being toxic to reproduction under “Category 1B” with the hazard statement of “H360 FD” in the European CLP regulation. This has prompted studies on boron-mediated reprotoxic effects in male workers in boron mining areas and boric acid production plants. By contrast, studies on boron-mediated developmental effects in females are scarce. The present study was designed to fill this gap. Hundred and ninety nine females residing in Bandirma and Bigadic participated in this study investigating pregnancy outcomes. The participants constituted a study group covering blood boron from low (< 100 ng B/g blood, n = 143) to high (> 150 ng B/g blood, n = 27) concentrations. The mean blood boron concentration and the mean estimated daily boron exposure of the high exposure group was 274.58 (151.81-975.66) ng B/g blood and 24.67 (10.47-57.86) mg B/day, respectively. In spite of the high level of daily boron exposure, boron-mediated adverse effects on induced abortion, spontaneous abortion (miscarriage), stillbirth, infant death, neonatal death, early neonatal death, preterm birth, congenital anomalies, sex ratio and birth weight of newborns were not observed. [ABSTRACT FROM AUTHOR]

11693179 12 Wright P, Kelsall J, Healing G. Differential expression of cyclin-dependent kinases in the adult human retina in relation to CDK inhibitor retinotoxicity. The strategy appears equally applicable to characterise other small molecule inhibitors with a risk of ocular toxicity, which appears to be of relevance with the increasing prevalence of clinical ocular toxicity, particularly for tyrosine kinase inhibitors. Retinotoxicity of chemicals has been an issue for the Archives of Toxicology since decades. [Extracted from the article]

An editorial is presented on arsenic research and its relevance to epidemiological and experimental toxicology. An overview of various contemporary trends in toxicological research on arsenic is provided. It expresses the view on how arsenic has played an eminent role in human poisoning and the association between prenatal arsenic exposure and development of diabetes mellitus.

Against this background, snake venom toxicology is a field of high toxicological impact that has attracted increased interest over the last decade. Inhibitory effect of snake venom toxin on NF-kappaB activity prevents human cervical cancer cell growth via increase of death receptor 3 and 5 expression. Snake venoms are complex natural secretions comprised of hundreds of different molecules with a wide range of biological functions, which after injection cause local and systemic toxic manifestations (Di Nicola [5]; Acunha et al [2]). From venom to drugs: a review and critical analysis of Indian snake venom toxins envisaged as anticancer drug prototypes. [Extracted from the article]

The authors summarize information related to drug metabolism-dependent toxicity. They present information from different articles and journals that cover the dynamic progress of drug metabolizing enzymes. The information focuses on nomenclature, substrate specifications, genetic organization, polymorphism, clinical relevance and role in carcinogenesis.

The N-acetyl- S-(1-carbamoyl-2-hydroxy-ethyl)- l-cysteine (iso-GAMA) could be identified as a further human metabolite of acrylamide. In this study, we report the excretion of d3-iso-GAMA in human urine after single oral administration of deuterium labelled acrylamide (d3-AA). One healthy male volunteer ingested a dose of about 1 mg d3-AA which is equivalent to a dose of 13 μg/kg bodyweight. Over a period of 46 h the urine was collected and the d3-iso-GAMA levels analysed by LC-ESI-MS/MS. The excretion of iso-GAMA begins five hours after application. It rises to a maximum concentration ( cmax) of 43 μg/l which was quantified in the urine excreted after 22 h ( tmax). The excretion pattern is parallel to that of the major oxidative metabolite N-acetyl- S-(2-carbamoyl-2-hydroxy-ethyl)- l-cysteine (GAMA). Total recovery of iso-GAMA was about 1% of the applied dose. Together with N-acetyl- S-(2-carbamoylethyl)- l-cysteine (AAMA) and GAMA, 57% of the applied dose is eliminated as mercapturic acids. The elimination kinetics of the three mercapturic acids of AA are compared. We show that dietary doses of acrylamide (AA) cause an overload of detoxification via AAMA and lead to the formation of carcinogenic glycidamide (GA) in the human body. [ABSTRACT FROM AUTHOR]

Cultured primary porcine urinary bladder epithelial cells (PUBEC) represent an adequate and easy to handle in vitro system for studies of urothelial toxicity. PUBEC maintain in vivo-like metabolic activities and physiological functions. They express inducible cytochrome P4501A isoenzymes, which are of particular relevance, since they contribute to activation of bladder carcinogens. A possible drawback of PUBEC is their isolation from common domestic pigs that do not represent an inbred strain. In order to further establish PUBEC as a standard in vitro toxicity test system we analysed possible interindividual differences in CYP1A1 inducibility. Interestingly, we observed by flow cytometry that PUBEC obtained from individual pigs consist of two distinct subpopulations with inducible and non-inducible cells. A strong, concentration-dependent CYP1A1 induction was observed in the responsive subpopulation when incubated with benzo[a]pyrene (B[a]P) in a concentration range between 1 and 10 μM. In contrast, no CYP1A1 induction was obtained in the non-responsive subpopulation up to the highest tested concentrations of 100 μM. The fraction of responsive cells showed large interindividual differences ranging from 10 to 65% of the total cell number. For practical purposes it might be reasonable to analyse pools of PUBEC from five pigs which substantially reduce batch to batch variability. In conclusion, we have identified two functionally distinct subpopulations of urinary bladder epithelial cells. It will be interesting to study whether the CYP1A inducible subtype is more susceptible to bladder carcinogens. [ABSTRACT FROM AUTHOR]

Aromatic amines have been shown to cause bladder cancer. However, epithelial cells of the urinary bladder, cells of origin of bladder cancer, may be exposed to numerous substances besides aromatic amines. In the present study, we analysed possible interactions between the aromatic amines 4-aminobiphenyl (4-ABP) as well as 2-naphthylamine (2-NA) and the polycyclic aromatic hydrocarbon benzo[a]pyrene (B[a]P). For this purpose we incubated primary porcine urinary bladder epithelial cells (PUBEC) with concentrations of 1 to 50 μM 4-ABP with and without co-exposure to B[a]P. As expected B[a]P increased mRNA expression of cytochrome P450 1A1 (CYP1A1), whereas 4-ABP had no effect. However, when co-exposed 4-ABP enhanced the induction of CYP1A1 by B[a]P. This result was confirmed by Western blot analysis of CYP1A1 protein expression. A similar effect as for CYP1A1 was also observed for cyclooxygenase-2 (COX-2) and UDP-glucuronosyltransferase 1 (UGT1). Next, we studied co-exposures of 2-NA and B[a]P. Similar as for 4-ABP also 2-NA enhanced B[a]P-mediated induction of CYP1A1. Our results demonstrate that some aromatic amines may enhance the influence of B[a]P on Ah receptor-dependent genes. [ABSTRACT FROM AUTHOR]

A concept relating the lipophilicity of chemicals with their genotoxicity on a chromosomal level had been generated by Schultz and Önfelt (Chem Biol Interact 126:97–123, 2000). It was shown that aneuploidy in Chinese hamster V79 cells was elicited by lipophilic chemicals at concentrations related to their hydrophobicity (log P), whereas toxicants with a specific mode of action acted at concentrations consistently lower than predicted based on log P. We have now combined available data sets on aneuploidy/micronucleus formation with procedures used in QSAR modelling, in order to find new molecular descriptors for modelling non-specific chromosomal genotoxicity, and to optimise combinations thereof. Molecular structures of 26 chemicals, including steroids, were converted into single 3D models using Corina (version 3.20), and 11 descriptors of molecular properties were calculated. The data of 16 compounds assigned to a non-specific mode of action were imported into the QSAR module of the software package Cerius2 (version 4.10). Applying genetic function approximation (GFA), linear equations were set up relating molecular descriptors with experimental concentrations at which doubling of micronuclei occurred in V79 cells (exp −log C). The number of variables (molecular descriptors) was limited to a maximum of three, and linear and quadratic terms were allowed. Based on the descriptions provided by the GFA procedure, log P was the most suitable single property to describe non-specific genotoxicity [ r 2 = 0.88], confirming the original concept of Schultz and Önfelt. Using more descriptors (up to three in combination) resulted in an optimization of correlations up to r 2 = 0.97. Such optimal correlation coefficients were obtained by combinations (a) of the numbers of hydrogen bond acceptors, the polar surface and total surface areas of molecules on one hand, and by (b) the dipole moment, polar surface and total surface descriptors on the other hand. In essence, the relation of polar surface to the total molecular surface appears pivotal to determine the non-specific chromosomal genotoxicity of lipophilic compounds. [ABSTRACT FROM AUTHOR]

The synthetic steroid tetrahydrogestrinone is a new “designer drug” and was recently detected to be illegally used in sports. It is chemically closely related to trenbolone that is known as an animal growth promoter. The potencies of trenbolone, tetrahydrogestrinone and testosterone to induce micronuclei in V79 cells in vitro were determined. CREST analysis was employed to differentiate between aneugenic or clastogenic mechanisms. Cytotoxicity and an influence on the cell cycle were assessed in parallel. Incubations with testosterone, at concentrations between 3 and 300 μM, failed to induce micronuclei. By contrast, tetrahydrogestrinone and trenbolone increased the rate of micronuclei significantly, up to a doubling of the micronuclei rate of untreated controls. Tetrahydrogestrinone and trenbolone displayed a bell-shaped dose-response curve, with maximal effects observed at 3 and 30 μM, respectively. The micronuclei induced by tetrahydrogestrinone and trenbolone were predominantly kinetochor (CREST) positive, pointing to an aneugenic mode of action. This may be related to the specific structure of both molecules with a system of activated double bonds. As the genotoxic effect of tetrahydrogestrinone at a chromosomal level appears at a low concentration range, it cannot be ruled out that tetrahydrogestrinone presents a genotoxic hazard on a chromosomal level under conditions of its current misuse in sports. [ABSTRACT FROM AUTHOR]

The genotyping of N-acetyltransferase 2 ( NAT2) by PCR/RFLP methods yields in a considerable percentage ambiguous results. To resolve this methodical problem a statistical approach was applied. PHASE v2.1.1, a statistical program for haplotype reconstruction was used to estimate haplotype pairs from NAT2 genotyping data, obtained by the analysis of seven single nucleotide polymorphisms relevant for Caucasians. In 1,011 out of 2,921 (35%) subjects the haplotype pairs were clearcut by the PCR/RFLP data only. For the majority of the data the applied method resulted in a multiplicity (2–4) of possible haplotype pairs. Haplotype reconstruction using PHASE v2.1.1 cleared this ambiguity in all cases but one, where an alternative haplotype pair was considered with a probability of 0.029. The estimation of the NAT2 haplotype is important because the assignment of the NAT2 alleles * 12A, * 12B, * 12C or * 13 to the rapid or slow NAT2 genotype has been discussed controversially. A clear assignment is indispensable in surveys of human bladder cancer caused by aromatic amine exposures. In conclusion, PHASE v2.1.1 software allowed an unambiguous haplotype reconstruction in 2,920 of 2,921 cases (>99.9%). [ABSTRACT FROM AUTHOR]

Setting standards, such as occupational exposure limits (OELs) for carcinogenic substances must consider modes of action. At the European Union level, the scientific committee on occupational exposure limits (SCOEL) has discussed a number of chemical carcinogens and has issued recommendations. For some carcinogens, health-based OELs were recommended, while quantitative assessments of carcinogenic risks were performed for others. For purposes of setting limits this led to the consideration of the following groups of carcinogens. (A) Non-threshold genotoxic carcinogens; for low-dose assessment of risk, the linear non-threshold (LNT) model appears appropriate. For these chemicals, regulations (risk management) may be based on the ALARA principle (“as low as reasonably achievable”), technical feasibility, and other socio-political considerations. (B) Genotoxic carcinogens, for which the existence of a threshold cannot be sufficiently supported at present. In these cases, the LNT model may be used as a default assumption, based on the scientific uncertainty. (C) Genotoxic carcinogens with a practical threshold, as supported by studies on mechanisms and/or toxicokinetics; health-based exposure limits may be based on an established NOAEL (no observed adverse effect level). (D) Non-genotoxic carcinogens and non-DNA-reactive carcinogens; for these compounds a true (“perfect”) threshold is associated with a clearly founded NOAEL. The mechanisms shown by tumour promoters, spindle poisons, topoisomerase II poisons and hormones are typical examples of this category. Health-based OELs are derived for carcinogens of groups C and D, while a risk assessment is carried out for carcinogens of groups A and B. Substantial progress is currently being made in the incorporation of new types of mechanistic data into these regulatory procedures. [ABSTRACT FROM AUTHOR]

In the following, important research lines of computational toxicology were the development and refinement of computational models for relevant toxicological endpoints, such as liver injury, cardiotoxicity, renal toxicity and genotoxicity (Ekins [6]). Computational toxicology and drug discovery in computational toxicology: methods and protocols. 10.1007/s00204-020-02669-7 10 Kar S, Leszczynski J. Exploration of chemical approaches to predict the toxicity of chemical mixtures. Alternative methods to safety studies in experimental animals: role in the risk assessment of chemicals under the new European Chemicals Legislation (REACH). [Extracted from the article]

In I Archives of Toxicology i , oxidative stress has been a matter of Editorials for years (Hengstler and Bolt [10]; Bolt and Hengstler [2]; Stewart et al. [17]; Bolt and Stewart [4]; Marchan [13]). The parallelism between products of oxidative stress and advanced glycation end products, together with associated methodologies, points to new ways for research into the biological complexity of endogenous and exogenous toxicants. 10.1146/annurev-food-030117-012441 7 Distler L, Georgiewa A, Kenkel I, Huppert J, Pischetsrieder M. Structure- and concentration-specific assessment of the physiological reactivity of alpha-dicarbonyl degradation products in peritoneal dialysis fluids. [Extracted from the article]

We investigated the human metabolism of AA to the mercapturic acids N-acetyl-S-(2-carbamoylethyl)- l-cysteine (AAMA) and N-(R/S)-acetyl-S-(2-carbamoyl-2-hydroxyethyl)- l-cysteine (GAMA) which are derived from AA itself and from its oxidative genotoxic metabolite glycidamide (GA), respectively. A healthy male volunteer received a single dose of about 1 mg deuterium-labelled acrylamide (d3-AA), representing 13 μg/kg body weight, in drinking water. Urine samples before dosing and within 46 h after the dose were analysed for d3-AAMA and d3-GAMA by LC-ESI-MS/MS. A first phase of increase in urinary concentration was found to last 18 h with a broad plateau between 8 and 18 h for AAMA, and 22 h for GAMA. Elimination half-lives of both AAMA and GAMA were estimated to be approximately 3.5 h for the first phase and more than 10 h up to few days for the second phase. Total recovery in urine after 24 h was about 51% as the sum of AAMA and GAMA and hereby well in accordance with former studies in rats. After 2 days AAMA, accounting for altogether 52% of the total AA dose, was the major metabolite of AA in humans. GAMA, accounting for 5%, appeared as a minor metabolite of AA. In humans we found a urinary ratio of 0.1 for GAMA/AAMA compared to previously reported values of 0.2 for rats and 0.5 for mice. Therefore, the metabolic fate of AA in humans was more similar to that in rats than in mice as already demonstrated in terms of the haemoglobin adducts. Consequently a genotoxic potency of AA mediated by GA could be supposed to be comparable in rats and humans. [ABSTRACT FROM AUTHOR]

Technical dinitrotoluene (consisting of 2,4- and 2,6-dinitrotoluene isomers) has been widely used as explosives. Both technical isomers are mutagenic in Salmonella typhimurium TA98 strains and carcinogenic in rodents. 2,4-dinitrotoluene shows a dose-dependency of malignant tumors of the kidneys, liver, and mammary glands in rats and mice. In this case report, we discuss a cluster of three cases of urothelial cancer amongst a group of about 60 workers exposed to dinitrotoluenes. The workers were employed in the manufacturing of nitrotoluene explosives in the former German Democratic Republic. The cases occurred within a period of 12 years (1990–2002) leading to a 15.9 fold higher incidence of cancer of the urinary bladder than of the federal state where the chemical factory was located. The observation of the cluster of urothelial cancer in persons highly exposed to nitrotoluenes underlines the putative human carcinogenicity of dinitrotoluenes with the human urothelium as a relevant target tissue. [ABSTRACT FROM AUTHOR]

A comparative study ofN-acetyltransferase 2 (NAT2) genotyping and phenotyping (caffeine test method) was performed on 211 persons to elucidate apparent discrepancies in the assignment ofNAT2*12andNAT2*13alleles which occur in the literature. The study used the standard procedures of genotyping (two PCR runs and application of seven restriction enzymes) and phenotyping (determination of the two caffeine metabolites 5-acetylamino-6-formylamino-3-methyluracil (AFMU) and 1-methylxanthine (1X)), as documented in detail and validated by the Deutsche Forschungsgemeinschaft. The data were consistent with an AFMU/1X molar ratio of 0.85 as cut-off point (antimode) between phenotypically slow and rapid acetylators. Under this provision, several R/S allele combinations did not comply, either fully or partly, with their associated phenotypes. In particular, there was a wide phenotypic overlap of the alleged rapid allele combination groups (i)NAT2*12A/*5A;NAT2*12C/*5D;NAT2*4/*5B, (ii)NAT2*13/*6B;NAT2*4/*6A, and (iii)NAT2*13/*7A;NAT2*4/*7B. These groups obviously contained both phenotypically rapid and slow acetylators. If one assumes that the presence of one “wild type” alleleNAT2*4defines a rapid acetylator the assignment of the allelesNAT2*12A,NAT2*12C, andNAT*13as determinants of a rapid acetylator phenotype must be questioned. This refers in particular to the nucleotide changes A803G (NAT2*12A,NAT2*12C) and C282T (NAT2*13). Based on discussions in the literature and the data presented here, there is accumulating evidence that current assignments of theNAT2*12andNAT2*13alleles as determinants of a rapid acetylator state should be reconsidered. [ABSTRACT FROM AUTHOR]

Objectives: Concern on human renal toxicity and carcinogenicity of trichloroethylene is based on findings of increased incidences of renal cell cancers in persons with long-lasting and high occupational exposures to this solvent. The full tumour development is likely to require promotional stimuli, by repetitive episodes of high peak exposures to trichloroethylene, leading to nephrotoxicity. This process is visualised by the excretion of tubular marker proteins in the urine of exposed persons. For this purpose, surveillance of α1-microglobulin excretion is being suggested by the Deutsche Forschungsgemeinschaft. Methods: The present study assessed the applicability of α1-microglobulin as a biomarker of proximal tubule damage in the prevention of nephrotoxicity by trichloroethylene exposures. For this purpose, α1-microglobulin excretions were assessed in trichloroethylene-exposed and non-exposed subgroups of both cases (diseased with renal cancer) and controls (not diseased with renal cancer) of a recent case-control study. Results: The median of α1- microglobulin excretions in non-exposed persons was below the detection limit, but it was clearly elevated in exposed persons. The Wilcoxon rank sum test showed a significant difference (P = 0.0090). Consistent with the underlying concept, renal cell cancer cases who had been exposed to trichloroethylene had higher α1-microglobulin excretions than non-exposed cases (P = 0.0005) and also had higher α1-microglobulin excretions than exposed controls (P = 0.0004). Of 20 trichloroethylene- exposed renal cell cancer cases only three (15%) displayed a normal α1-microglobulin excretion of <5 mg/l. By contrast, 41(52%) out of 79 non-exposed renal cancer cases showed normal excretions of the biomarker. Conclusion: The present data are in agreement with the concept of pathogenesis of renal cell cancers developing under high (suggested: > 500 ppm peak exposures) and long-term (several years) exposure to trichloroethylene. They also visualise the potential value of α1-microglobulin excretion as a routine biomarker of renal toxicity that may be used in the medical surveillance of trichloroethylene-exposed persons. [ABSTRACT FROM AUTHOR]

Human metabolism of di(2-ethylhexyl)phthalate (DEHP) was studied after a single oral dose of 48.1 mg to a male volunteer. To avoid interference by background exposure the D4-ring-labelled DEHP analogue was dosed. Excretion of three metabolites, mono(2-ethyl-5-hydroxyhexyl)phthalate (5OH-MEHP), mono(2-ethyl-5-oxohexyl)phthalate (5oxo-MEHP) and mono(2-ethylhexyl)phthalate (MEHP), was monitored for 44 h in urine and for 8 h in serum. Peak concentrations of all metabolites were found in serum after 2 h and in urine after 2 h (MEHP) and after 4 h (5OH-MEHP and 5oxo-MEHP). While the major metabolite in serum was MEHP, the major metabolite in urine was 5OH-MEHP, followed by 5oxo-MEHP and MEHP. Excretion in urine followed a multi-phase elimination model. After an absorption and distribution phase of 4 to 8 h, half-life times of excretion in the first elimination phase were approximately 2 h with slightly higher half-life times for 5OH- and 5oxo-MEHP. Half-life times in the second phase—beginning 14 to 18 h post dose—were 5 h for MEHP and 10 h for 5OH-MEHP and 5oxo-MEHP. In the time window 36 to 44 h, no decrease in excreted concentrations of 5OH- and 5oxo-MEHP was observed. In the first elimination phase (8 to 14 h post dose), mean excretion ratios of MEHP to 5oxo-MEHP and MEHP to 5OH-MEHP were 1 to 1.8 and 1 to 3.1. In the second elimination phase up to 24 h post dose mean excretion ratios of MEHP to 5oxo-MEHP to 5OH-MEHP were 1 to 5.0 to 9.3. The excretion ratio of 5OH-MEHP to 5oxo-MEHP remained constant through time at 1.7 in the mean. After 44 h, 47% of the DEHP dose was excreted in urine, comprising MEHP (7.3%), 5OH-MEHP (24.7%) and 5oxo-MEHP (14.9%). [ABSTRACT FROM AUTHOR]

Occupational exposure is definitely a major cause of cancer. In the field of urology, the urinary bladder is the most important target. A classical cause of bladder cancer is exposure to carcinogenic aromatic amines, especially benzidine and β-naphthylamine. Such exposures were related to work places in the chemical industry, implying production and processing of classical aromatic amines, and in the rubber industry. Occupational bladder cancer has also been observed in dyers, painters and hairdressers. Even some occupations with much lower exposures to carcinogenic aromatic amines, like coke oven workers or workers in the rubber industry after the ban on β-naphthylamine, are at risk. In these occupations, exposure to complex mixtures of substances containing combustion products (e.g. polycyclic aromatic hydrocarbons) or nitrosamines is common. Renal cell cancer has been observed as an occupational disease in cases of very high exposure to trichloroethylene having led to narcotic or prenarcotic symptoms. Occupationally related cancers of the prostate or the testes appear currently not relevant. [ABSTRACT FROM AUTHOR]

In order to investigate the chromosomal genotoxicity of nitrobenzene and benzonitrile, we studied the induction of micronuclei (MN) by these test compounds in V79 cells, as well as effects on the formation and stability of microtubules and on motor protein functions. No cytotoxicity was seen in V79 cell cultures in terms of Neutral red uptake after 18 h treatment with up to 1 mM nitrobenzene or 1 mM benzonitrile. Subsequently, a concentration range up to 100 µM was used in the experiments on induction of MN. Both test compounds exhibit a weak, but definitely positive test result compared to the solvent (DMSO) control. Minimal effect concentrations of nitrobenzene and benzonitrile appeared as low as 0.01 µM, and no-effect-concentrations were between 0.001 and 0.005 µM. Clearly enhanced MN rates were found at 0.1 µM and higher. Both, nitrobenzene and benzonitrile, induced mostly kinetochor (CREST)-positive micronuclei, thus characterising the chromosomal effects as aneugenic. In cell-free assays, a slight effect on tubulin assembly was observed at 1 mM nitrobenzene without addition of DMSO. Higher concentrations (5 mM) led to secondary effects. In presence of 1% DMSO, nitrobenzene exerted no detectable effect on tubulin assembly up to the solubility limit in water of about 15 mM. For benzonitrile in presence of DMSO, a clear dose–response of inhibition of tubulin assembly at 37°C was seen above the no-effect-concentration of 2 mM, with an IC50 of 13 mM and protein denaturation starting above a level of about 20 mM. The nature of the effects of nitrobenzene and benzonitrile on the association of tubulin to form microtubules was confirmed by electron microscopy. Treatment by either 5 mM nitrobenzene or 13 mM benzonitrile plus 1% DMSO left the microtubular structure intact whereas 5 mM nitrobenzene, in absence of DMSO, led to irregular cluster formations. The experiments demonstrate that both nitrobenzene and benzonitrile, in millimolar concentration ranges, may lead to interference with tubulin assembly in a cell-free system. The functionality of the tubulin–kinesin motor protein system was assessed using the microtubule gliding assay. Nitrobenzene affected the gliding velocity in a concentration-dependent manner, starting at about 7.5 µM and reaching complete inhibition of motility at 30 µM, whereas benzonitrile up to 200 µM did not affect the kinesin-driven gliding velocity. The micronucleus assay data demonstrate a chromosomal endpoint of genotoxicity of nitrobenzene and benzonitrile. Aneugenic effects of both compounds occur at remarkably low concentrations, with lowest-effect-concentrations being 0.1 µM. This points to the relevance of interactions with the cellular spindle apparatus. [ABSTRACT FROM AUTHOR]

The importance of the isoform CYP2E1 of the human cytochrome P-450 superfamily of enzymes for occupational and environmental medicine is derived from its unique substrate spectrum that includes a number of highly important high-production chemicals, such as aliphatic and aromatic hydrocarbons, solvents and industrial monomers (i.a. alkanes, alkenes, aromatic and halogenated hydrocarbons). Many polymorphic genes, such as CYP2E1, show considerable differences in allelic distribution between different human populations. The polymorphic nature of the human CYP2E1 gene is significant for inter-individual differences in toxicity of its substrates. Since the substrate spectrum of CYP2E1 includes many compounds of basic relevance to industrial toxicology, a rationale for metabolic interactions of different CYP2E1 substrates is provided. In-depth research into the inter-individual phenotypic differences of human CYP2E1 enzyme activities was enabled by the recognition that the 6-hydroxylation of the drug chlorzoxazone is mediated by CYP2E1. Studies on CYP2E1 phenotyping have pointed to inter-individual variations in enzyme activities. There are consistent ethnic differences in CYP2E1 enzyme expression, mostly demonstrated between European and Japanese populations, which point to a major impact of genetic factors. The most frequently studied genetic polymorphisms are the restriction fragment length polymorphisms PstI/RsaI (mutant allele: CYP2E1*5B) located in the 5'-flanking region of the gene, as well as the DraI polymorphism (mutant allele: CYP2E1*6) located in intron 6. These polymorphisms are partly related, as they form the common allele designated CYP2E1*5A. Striking inter-ethnic differences between Europeans and Asians appear with respect to the frequencies of the CYP2E1*5A allele (only approximately 5% of Europeans are heterozygous, but 37% of Asians are, whilst 6% of Asians are homozygous). Available studies indicate a wide variation in human CYP2E1 expression, which are very likely based on complex gene–environment interactions. Major inter-ethnic differences are apparent on the genotyping and the phenotyping levels. Selected cases are presented where inter-ethnic variations of CYP2E1 may provide likely explanations for unexplained findings concerning industrial chemicals that are CYP2E1 substrates. Possible consequences of differential inter-individual and inter-ethnic susceptibilities are related to individual expressions of clinical symptoms of chemical toxicity, to results of biological monitoring of exposed workers, and to the interpretation of results of epidemiological or molecular-epidemiological studies. [ABSTRACT FROM AUTHOR]

Tobacco-associated carcinogens are catalyzed by microsomal epoxide hydrolase (mEH). Combinations of the Y113H and H139R polymorphic EPHX1 variants have been assumed to alter the enzyme activity and thus the risk of squamous cell head and neck cancer (SCCHN). Based on in vitro data, a putative low, medium and high mEH activity has been associated with combinations of these genotypes, and the respective activity categories have been frequently used in the estimation of risks for smoking-related cancers. We investigated the SCCHN risk for EPHX1 genotypes among 280 cases and 289 controls. We could not detect main effects of the EPHX1 genotypes, but a smaller risk of the 139HR genotype in smokers (odds ratio, OR, 0.57; 95% confidence interval, CI, 0.34–0.95). We could not confirm an increase of the SCCHN risk for genotype combinations according to a putative medium and high enzyme activity (OR 1.28, 95% CI 0.84–1.96; OR 0.98, 95% CI 0.58–1.64, respectively), but a significant heterogeneity of the estimated risks for the singular genotypes within these categories among smokers (P=0.02). Further, p53 mutations among smoking cases were less frequent in the group with a putative high enzyme activity, although insignificant due to small numbers (OR 0.54, 95% CI 0.13–2.17). This supports uncertainties in categorizing genotypes with respect to limited enzyme activity data, especially when taken from in vitro experiments. [ABSTRACT FROM AUTHOR]

Alcohol consumption and tobacco smoking are major causes of head and neck cancers, and regional differences point to the importance of research into gene-environment interactions. Much interest has been focused on polymorphisms of CYP1A1 and of GSTM1 and GSTT1, but a number of studies have not demonstrated significant effects. This has mostly been ascribed to small sample sizes. In general, the impact of polymorphisms of metabolic enzymes appears inconsistent, with some reports of weak-to-moderate associations, and with others of no elevation of risks. The classical cytochrome P450 isoenzyme considered for metabolic activation of polycyclic aromatic hydrocarbons (PAH) is CYP1A1. A new member of the CYP1 family, CYP1B1, was cloned in 1994, currently representing the only member of the CYP1B subfamily. A number of single nucleotide polymorphisms of the CYP1B1 gene have been reported. The amino acid substitutions Val432Leu (CYP1B1*3) and Asn453Ser (CYP1B1*4), located in the heme binding domain of CYP1B1, appear as likely candidates to be linked with biological effects. CYP1B1 activates a wide range of PAH, aromatic and heterocyclic amines. Very recently, the CYP1B1 codon 432 polymorphism (CYP1B1*3) has been identified as a susceptibility factor in smoking-related head-and-neck squamous cell cancer. The impact of this polymorphic variant of CYP1B1 on cancer risk was also reflected by an association with the frequency of somatic mutations of the p53 gene. Combined genotype analysis of CYP1B1 and the glutathione transferases GSTM1 or GSTT1 has pointed to interactive effects. This provides new molecular evidence that tobacco smoke-specific compounds relevant to head and neck carcinogenesis are metabolically activated through CYP1B1 and is consistent with a major pathogenetic relevance of PAH as ingredients of tobacco smoke. [ABSTRACT FROM AUTHOR]

Risk assessments of synthetic chemicals with oestrogen-like activity must take into account the high dietary levels of natural endocrine modulators in food. In view of current regulations of the European Union, a hygiene-based margin of safety (HBMOS) for xeno-oestrogens was defined as a quotient of estimated human daily intakes weighted by relative rodent in vivo potencies of the compounds. Such comparisons of intakes and potencies of natural isoflavones, with short half-lives, with those of polychlorinated organic pollutants (POP) displaying significant toxicokinetic accumulation, deserves the special consideration of toxicokinetics. For slowly accumulating compounds such comparison is much more favourable when based on comparative blood and tissue levels, not on scenarios of daily exposures. Observing these principles, the present communication extends the HBMOS concept to POP, using o,p'-DDT, the oestrogenic component of DDT mixtures, as a prototype. An HBMOS of 137 is derived for o,p'-DDT indicative of a sufficient margin of safety to ensure the absence of risk to human health due to its hormonal action, under exposure conditions now prevailing in Western countries. [ABSTRACT FROM AUTHOR]

The high priority of monitoring workers exposed to nitrobenzene is a consequence of clear findings of experimental carcinogenicity of nitrobenzene and the associated evaluations by the International Agency for Research on Cancer. Eighty male employees of a nitrobenzene reduction plant, with potential skin contact with nitrobenzene and aniline, participated in a current medical surveillance programme. Blood samples were routinely taken and analysed for aniline, 4-aminodiphenyl (4-ADP) and benzidine adducts of haemoglobin (Hb) and human serum albumin (HSA). Also, levels of methaemoglobin (Met-Hb) and of carbon monoxide haemoglobin (CO-Hb) were monitored. Effects of smoking were straightforward. Using the rank sum test of Wilcoxon, we found that very clear-cut and statistically significant smoking effects (about 3-fold increases) were apparent on CO-Hb (P=0.00085) and on the Hb adduct of 4-ADP (P=0.0006). The mean aniline-Hb adduct level in smokers was 1.5 times higher than in non-smokers; the significance (P=0.05375) was close to the 5% level. The strongest correlation was evident between the Hb and HSA adducts of aniline (rs=0.846). Less pronounced correlations (but with P values < 0.02) appeared between aniline-Hb and 4-ADP-Hb adducts (rs=0.388), between 4-ADP and 4-ADP-HSA adducts (rs=0.373), and between 4-ADP-Hb and aniline-HSA adducts (rs=0.275). In view of the proposal for additional use of the aniline-HSA adduct for biological monitoring, particularly in cases of acute overexposures or poisonings, the strong correlation of the Hb and HSA conjugates is noteworthy; the ratio aniline-HSA:aniline-Hb was 1:42 for the entire cohort. [ABSTRACT FROM AUTHOR]

In view of the established extrapulmonary cancer sites targeted by smoking a multiplicity of compounds and mechanisms might be involved. It has been debated that smoking caused increased incidence of N-methylvaline at the N-terminus of haemoglobin. Because this could indicate a relevance of methylating nitrosamines in tobacco smoke, data are presented from an industrial cohort of 35 smokers and 21 non-smokers repeatedly monitored between 1994 and 1999. In general, N-methylvaline adduct levels in haemoglobin of smokers were approximately 50% higher than those of non-smokers. The smoking-induced methylation of haemoglobin is likely to be caused by dimethylnitrosamine (N-nitroso-dimethylamine), a major nitrosamine in side-stream tobacco smoke. The biomonitoring data emphasise the potential value of N-methylvaline as a smoking-related biomarker and call for intensified research on tobacco smoke compounds that lead to macromolecular methylation processes. [ABSTRACT FROM AUTHOR]

In general, the biological activation of nephrocarcinogenic chlorinated hydrocarbons proceeds via conjugation with glutathione. It has mostly been assumed that the main site of initial conjugation is the liver, followed by a mandatory transfer of intermediates to the kidney. It was therefore of interest to study the enzyme activities of subgroups of glutathione transferases (GSTs) in renal cancers and the surrounding normal renal tissues of the same individuals (n=21). For genotyping the individuals with respect to known polymorphic GST isozymes the following substrates with differential specificity were used: 1-chloro-2,4-dinitrobenzene for overall GST activity (except GST θ); 7-chloro-4-nitrobenzo-2-oxa-1,3-diazole for GST α; 1,2-dichloro-4-nitro-benzene for GST µ; ethacrynic acid and 4-vinylpyridine for GST π; and methyl chloride for GST θ. In general, the normal tissues were able to metabolize the test substrates. A general decrease in individual GST enzyme activities was apparent in the course of cancerization, and in some (exceptional) cases individual activities, expressed in the normal renal tissue, were lost in the tumour tissue. The GST enzyme activities in tumours were independent of tumour stage, or the age and gender of the patients. There was little influence of known polymorphisms of GSTM1, GSTM3 and GSTP1 upon the activities towards the test substrates, whereas the influence of GSTT1 polymorphism on the activity towads methyl chloride was straightforward. In general, the present findings support the concept that the initial GST-dependent bioactivation step of nephrocarcinogenic chlorinated hydrocarbons may take place in the kidney itself. This should be a consideration in toxicokinetic modelling. [ABSTRACT FROM AUTHOR]

A novel concept – the hygiene-based margin of safety (HBMOS) – is suggested for the assessment of the impact of potential endocrine modulators. It integrates exposure scenarios and potency data for industrial chemicals and naturally occurring dietary compounds with oestrogenic activity. An HBMOS is defined as a quotient of estimated daily intakes weighted by the relative in vivo potencies of these compounds. The Existing Chemicals Programme of the European Union provides Human and Environmental Risk Assessments of Existing Chemicals which include human exposure scenarios. Such exposure scenarios, along with potency estimates for endocrine activities, may provide a basis for a quantitative comparison of the potential endocrine-modulating effects of industrial chemicals with endocrine modulators as natural constituents of human diet. Natural phyto-oestrogens exhibit oestrogenic activity in vitro and in vivo. Important phyto-oestrogens for humans are isoflavones (daidzein, genistein) and lignans, with the highest quantities found in soybeans and flaxseed, respectively. Daily isoflavone exposures calculated for infants on soy-based formulae were in the ranges of 4.5–8 mg/kg body wt.; estimates for adults range up to 1 mg/kg body wt. The Senate Commission on the Evaluation of Food Safety (SKLM) of the Deutsche Forschungsgemeinschaft has also indicated a wide range of dietary exposures. For matters of risk assessment, the SKLM has based recommendations on dietary exposure scenarios, implying a daily intake of phyto-oestrogens in the order of 1 mg/kg body wt. On the basis of information compiled within the Existing Chemicals Programme of the EU, it appears that a daily human exposure to nonylphenol of 2 µg/kg body wt. may be a worst-case assumption, but which is based on valid scenarios. The intake of octylphenol is much lower, due to a different use pattern and applications, and may be neglected. Data from migration studies led to estimations of the daily human uptake of bisphenol A of maximally 1 µg/kg body wt. On the basis of comparative data from uterotrophic assays in rats, with three consecutive days of oral applications involved, and taking the natural phyto-oestrogen daidzein as reference (=1), relative uterotrophic activities in DA/Han rats follow the sequence: daidzein = 1; bisphenol A = 1; p-tert-octylphenol = 2; o,p'-DDT = 4; ethinyl oestradiol = 40,000. The derived values from exposure scenarios, as well as these relative potency values and bridging assumptions, led to calculations of HBMOS as a quantitative comparison of potential endocrine-modulating effects of industrial chemicals with those of natural constituents of human diet. HBMOS estimates for nonylphenol ranged between 250 and 500, dependent on bridging assumptions, and around 1000 for bisphenol A. The derivations of HBMOS were in full support of the conclusions reached by the SKLM of the Deutsche Forschungsgemeinschaft. The estimated HBMOS values for the industrial chemicals (nonylphenol, bisphenol A) appear sufficiently high to ensure the absence of a practical risk to human health under the present exposure conditions. [ABSTRACT FROM AUTHOR]

The collagen gel sandwich culture of hepatocytes has been proposed as one of the most suitable culture models available for biotransformation studies of xenobiotics. It is a complex model which imitates the cascade of enzymatic events of in vivo biotransformation and allows investigation of biological endpoints under realistic conditions. The biotransformation of trichloroethylene (TRI) has been studied in this model using rat hepatocytes. Headspace gas chromatographic measurements revealed that hepatocytes, cultured for 4 days in this in vitro system, metabolised TRI into the major oxidative metabolites trichloroacetic acid (TCA) and trichloroethanol (TCE). Cultured hepatocytes were exposed either to TRI, or to TCA and TCE. Endpoints studied were albumin secretion and the cytochrome P450 (CYP)-dependent enzymatic activities ethoxyresorufin O-deethylase (EROD), pentoxyresorufin O-depentylase (PROD) and N-nitrosodimethylamine demethylase (NDMA). The results show that both the parent compound and its metabolites exert specific effects on different CYP-dependent mono-oxygenase activities, as seen in vivo. It is suggested that collagen gel sandwich cultures represent a useful in vitro model for the investigation of metabolism-linked toxicity studies. [ABSTRACT FROM AUTHOR]

Bisphenol A [BPA; 2,2-bis-(4-hydroxyphenyl)-propane] is a monomer used in the manufacture of resins with a wide range of applications, e.g. plastic coatings in the food packaging industry. BPA has been shown to have a weak oestrogenic activity in vitro and in vivo. Despite its low oestrogenic potency there is concern that, as a consequence of slow clearance, BPA might reach biologically significant levels in humans and animals exposed to environmental levels. To address this concern, we assessed the kinetic behaviour of BPA in female DA/Han rats. Groups of female rats received 10 mg BPA/kg body weight intravenously or 10 or 100 mg BPA/kg body weight orally (by gavage). Blood samples were collected at different time-points and plasma was prepared. Free BPA in the samples was isolated by fluid-fluid extraction. BPA was measured by GC-MS which allowed the reliable determination of BPA concentrations as low as approximately 10 ng/ml plasma. Immediately after i.v. administration, the BPA plasma concentration was in the range of about 15 µg/ml and decreased rapidly within the first hour (to 700 ng/ml). The levels declined further (100 ng/ml at 2 h), and after 24 h the analytical detection limit was reached. BPA was detected in plasma as early as 10 min after gavage administration, indicating rapid initial uptake from the gastrointestinal tract. Absorption of BPA was variable. In animals receiving 10 mg/kg, maximal plasma levels were reached after 1.5 h (31 ng/ml) and 6 h (40 ng/ml). In animals receiving 100 mg/kg, plasma levels reached maxima around 30 min (150 ng/ml) and 3 h (134 ng/ml) after administration. After 48 h BPA was at or below the detection limit in both dose groups. Fluctuations in the BPA plasma concentrations over time point to the possibility of enterohepatic recirculation and protracted absorption from the gastrointestinal tract. Using the area under the concentration-time curves (AUCs), low bioavailabilities of 16.4% and 5.6% were calculated for the 10 and 100 mg/kg dose groups, respectively. The toxicokinetic properties of BPA in DA/Han rats are in agreement with the hypothesis of a rapid first-pass elimination by the liver and efficient metabolic clearance of low oral doses. Only excessive doses may lead to bioaccumulation if detoxification pathways are saturated. [ABSTRACT FROM AUTHOR]

The high acute toxicity of acrylonitrile may be a result of its intrinsic biological reactivity or of its metabolite cyanide. Intravenous N-acetylcysteine has been recommended for treatment of accidental intoxications in acrylonitrile workers, but such recommendations vary internationally. Acrylonitrile is metabolized in humans and experimental animals via two competing pathways; the glutathione-dependent pathway is considered to represent an avenue of detoxication whilst the oxidative pathway leads to a genotoxic epoxide, cyanoethylene oxide, and to elimination of cyanide. Cases of acute acrylonitrile overexposure or intoxication have occurred within persons having industrial contact with acrylonitrile; the route of exposure was by inhalation and/or by skin contact. The combined observations lead to the conclusion of a much higher impact of the oxidative metabolism of acrylonitrile in humans than in rodents. This is confirmed by differences in the clinical picture of acute life-threatening intoxications in both species, as well as by differential efficacies of antidotes. A combination of N-acetylcysteine with sodium thiosulfate seems an appropriate measure for antidote therapy of acute acrylonitrile intoxications. Clinical observations also highlight the practical importance of human individual susceptibility differences. Furthermore, differential adduct monitoring, assessing protein adducts with different rates of decay, enables the development of more elaborated biological monitoring strategies for the surveillance of workers with potential acrylonitrile contact. [ABSTRACT FROM AUTHOR]