Abstract  OBJECTIVES: This community based case-referent study was initiated to investigate aetiological factors for squamous cell carcinoma of the upper gastrointestinal tract. METHODS: The study was based on all Swedish men aged 40-79 living in two regions of Sweden during 1988-90. Within that base, efforts were made to identify all incident cases of squamous cell carcinoma of the oral cavity, oropharynx and hypopharynx, larynx, and oesophagus. Referents were selected as a stratified (age, region) random sample of the base. The response was 90% among cases and 85% among referents. There were 545 cases and 641 referents in the final study group. The study subjects were interviewed about several lifestyle factors and a life history of occupations and work tasks. The exposure to 17 specific agents were coded by an occupational hygienist. The relative risk (RR) of cancer was calculated by logistic regression, standardising for age, geographical region, and alcohol and tobacco consumption. RESULTS: Exposure to asbestos was associated with an increased risk of laryngeal cancer, and a dose-response relation was present. The RR was 1.8 (95% confidence interval (95% CI) 1.1 to 3.0) in the highest exposure group. More than eight years of exposure to welding fumes was associated with an increased risk of pharyngeal cancer (RR 2.3 (1.1 to 4.7)), and laryngeal cancer (RR 2.0 (1.0 to 3.7)). There were indications of a dose-response for duration of exposure. Associations were also found for high exposure to polycyclic aromatic hydrocarbons (PAHs) and oesophageal cancer, RR 1.9 (1.1 to 3.2). Exposure to wood dust was associated with a decreased risk of cancer at the studied sites. CONCLUSIONS: Some of the present findings confirm known or suspected associations--such as asbestos and laryngeal cancer. The study indicates that welding may cause an increased risk of pharyngeal as well as laryngeal cancer. The findings corroborate an association between exposure to PAHs and oesophageal cancer.

Abstract  UDP-glucuronosyltransferase (UGT) enzymes comprise a superfamily of key proteins that catalyze the glucuronidation reaction on a wide range of structurally diverse endogenous and exogenous chemicals. Glucuronidation is one of the major phase II drug-metabolizing reactions that contributes to drug biotransformation. This biochemical process is also involved in the protection against environmental toxicants, carcinogens, dietary toxins and participates in the homeostasis of numerous endogenous molecules, including bilirubin, steroid hormones and biliary acids. Over the years, significant progress was made in the field of glucuronidation, especially with regard to the identification of human UGTs, study of their tissue distribution and substrate specificities. More recently, the degree of allelic diversity has also been revealed for several human UGT genes. Some polymorphic UGTs have demonstrated a significant pharmacological impact in addition to being relevant to drug-induced adverse reactions and cancer susceptibility. This review focuses on human UGTs, the description of the nature of polymorphic variations and their functional impact. The pharmacogenomic implication of polymorphic UGTs is presented, more specifically the role of UGT polymorphisms in modifying cancer risk and their impact on individual risk to drug-induced toxicities.

Abstract  Guideline developers around the world are inconsistent in how they rate quality of evidence and grade strength of recommendations. As a result, guideline users face challenges in understanding the messages that grading systems try to communicate. Since 2006 the BMJ has requested in its “Instructions to Authors” on bmj.com that authors should preferably use the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system for grading evidence when submitting a clinical guidelines article. What was behind this decision? In this first in a series of five articles we will explain why many organisations use formal systems to grade evidence and recommendations and why this is important for clinicians; we will focus on the GRADE approach to recommendations. In the next two articles we will examine how the GRADE system categorises quality of evidence and strength of recommendations. The final two articles will focus on recommendations for diagnostic tests and GRADE’s framework for tackling the impact of interventions on use of resources. GRADE has advantages over previous rating systems. Other systems share some of these advantages, but none, other than GRADE, combines them all.

Abstract  Inner-city, minority populations are high-risk groups for adverse birth outcomes and also are more likely to be exposed to environmental contaminants, including environmental tobacco smoke (ETS), benzo[a]pyrene (BaP), and other polycyclic aromatic hydrocarbons (PAHs) found in urban air. In a sample of nonsmoking African-American and Dominican women, we evaluated the effects on birth outcomes of prenatal exposure to ETS, using questionnaire data and plasma cotinine as a biomarker of exposure, and environmental PAHs using BaP-DNA adducts as a molecular dosimeter. We previously reported that among African Americans, high prenatal exposure to PAHs estimated by prenatal personal air monitoring was associated with lower birth weight (p = 0.003) and smaller head circumference (p = 0.01) after adjusting for potential confounders. In the present analysis, self-reported ETS was associated with decreased head circumference (p = 0.04). BaP-DNA adducts were not correlated with ETS or dietary PAHs. There was no main effect of BaP-DNA adducts on birth outcomes. However, there was a significant interaction between the two pollutants such that the combined exposure to high ETS and high adducts had a significant multiplicative effect on birth weight (p = 0.04) and head circumference (p = 0.01) after adjusting for ethnicity, sex of newborns, maternal body mass index, dietary PAHs, and gestational age. This study provides evidence that combined exposure to environmental pollutants at levels currently encountered in New York City adversely affects fetal development.

Abstract  The public depends on competent risk assessment from the federal government and the scientific community to grapple with the threat of pollution. When risk reports turn out to be overblown--or when risks are overlooked--public skepticism abounds. This comprehensive and readable book explores how the U.S. Environmental Protection Agency (EPA) can improve its risk assessment practices, with a focus on implementation of the 1990 Clean Air Act Amendments. With a wealth of detailed information, pertinent examples, and revealing analysis, the volume explores the "default option" and other basic concepts. It offers two views of EPA operations: The first examines how EPA currently assesses exposure to hazardous air pollutants, evaluates the toxicity of a substance, and characterizes the risk to the public. The second, more holistic, view explores how EPA can improve in several critical areas of risk assessment by focusing on cross-cutting themes and incorporating more scientific judgment. This comprehensive volume will be important to the EPA and other agencies, risk managers, environmental advocates, scientists, faculty, students, and concerned individuals.

Abstract  Hygroscopic aerosols grow in size as they are inhaled into the humid airways. An empirical formula describing the growth rate is derived from the results of an exact calculation. The approximate particle growth relation is used to calculate total and regional depositions of dry NaCl aerosols in the human respiratory tract for initial particle diameters ranging from 0.01 to 10 μm. Assuming a relative humidity of 99.5% in the airways, total deposition results are found to be in good agreement with recent experimental data, and show a minimum deposition near 0.08 μm. For particles with an initial diameter larger than 0.2 μm, it is found that total deposition is increased due to particle hygroscopicity, whereas an opposite trend is seen for particles initially smaller than 0.2 μm. In most cases, deposition patterns vary appreciably due to the growth of the particles.

Abstract  Mortality and cancer incidence was investigated among the 695 bus garage workers employed as mechanics, servicemen, or hostlers for at least six months in five bus garages in Stockholm between 1945 and 1970. The exposure to diesel exhaust and asbestos was estimated by industrial hygienists. A small excess of lung cancer mortality was found in the cohort when occupationally active men in Stockholm were used as the reference group. A case-referent study was performed within the cohort, six referents being selected for each of the 20 lung cancer cases. The lung cancer risk increased with increasing cumulative exposure to diesel exhaust, but not with cumulative asbestos exposure. The relative risk for lung cancer among the highly exposed men was 2.4 (95% CI 1.3-4.5) as compared with those with low exposure. The study indicates that exposure to diesel exhaust increases the risk for lung cancer.

Abstract  A Workshop on the Qualitative and Quantitative Comparability of Human and Animal Developmental Neurotoxicity was held in Williamsburg, Va. on April 11-13, 1989. Based upon data presented at the Workshop, the degree of qualitative and quantitative comparability between data obtained from humans and experimental animals is reviewed for several developmental neurotoxicants (lead, agents of abuse, alcohol, PCBs, phenytoin, methylmercury, and ionizing radiation). Qualitative comparability was considered for the following functional categories: motor development and function, cognitive function, sensory function, motivation/arousal behavior, and social behavior. Quantitative comparability was assessed by comparing administered dose as well as measures of internal dose (e.g., blood levels) for selected agents. Comparability of qualitative changes between humans and rodents was most apparent when comparisons were made on the basis of general categories of behavioral function. These data support the use of animal models in assessing risk for developmental neurotoxicants and provide guidance on the types of functional end points that can be incorporated into a developmental neurotoxicity testing battery. Evidence of quantitative comparability was most apparent when an internal measure of dose (e.g., blood level) was used.

Abstract  National Center for Toxicological Research; Electric Power Research Institute. #Current methods to estimate the quantitative cancer risk of complex mixtures of polycyclic aromatic hydrocarbons (PAH) such as coal tar assume that overall potency can be derived from knowledge of the concentration of a few carcinogenic components such as benzo[a] pyrene (B[a]P). Genotoxic damage, such as DNA adducts, is thought to be an essential aspect of PAH-induced tumorigenesis and could be a biomarker for exposure useful for estimating risk. However, the role of B[a]P and the relationship of adduct formation in tumorigenosis have not been tested rigorously in models appropriate for human health risk assessment. Therefore, we directly compared tumor induction and adduct formation by B[a]P and coal tars in several experimental protocols, including one broadly accepted and used by regulators. We found that B[a]P content did not account for tumor incidences after exposure to coal tars. DNA adducts were found in both tumors and tumor-free tissue and tumor outcomes were not predicted by either quantitation of total DNA adducts or by the DNA adduct formed by B[a]P. These data suggest that risk assessments based on B[a]P content may not predict accurately risk to human health posed by environmental PAH.

Abstract  Summary A metabolic activation system with rat-liver microsome fraction plus cofactors (S9 mix) was applied to chromosomal aberration tests in vitro for the screening of chemical mutagens or carcinogens in the environment. Dialkylnitrosamines only induced chromosomal aberrations in Chinese hamster cells (CHL) when treated with S9 mix. The incidence of chromosomal aberrations in CHL varied with experimental conditions, e.g. incubation time, recovery time, components of S9 mix and inducers used for preparation of S9. For dimethylnitrosamine (DMN), the maximal incidence was obtained when the cells were incubated with S9 mix for 3 h and harvested 24 h after treatment. Therefore, this system (3 h incubation and 24 h recovery) was routinely applied to further screening of other chemicals with S9 prepared from PCB-pretreated rats. 10 carcinogens (e.g. 7,12-dimethylbenz[a]anthracene, benzo-[a]pyrene, quinoline, etc.) out of 16 induced aberrations when they were treated with S9 mix, whereas the remaining 6 carcinogens (e.g., 3-methyl-cholanthrene, 4-o-tolylazo-o-toluidine, etc.) induced few or no aberrations even after activation. Two insecticides, allethrin and diazinon, were strongly positive at relatively low doses only when they were activated with the S9 mix. Medical drugs, such as ethenzamide, methyl p-hydroxybenzoate and nitrofurazone, and a food additive, sodium hypochlorite, were positive on activation. Chemicals used for industry, such as styrene monomer and tris-dichloropropylphosphate,were also positive in our activation system.

Abstract  Diesel exhaust particles (DEP) were reported to have adverse effects on the immune system of laboratory animals and to induce thymic involution, particularly when exposure occurred during the fetal or lactational period. DEP consist of a carbon core to which many organic compounds are adsorbed, including polyaromatic hydrocarbons (PAHs) and their derivatives (e.g., dioxins and quinones). Although it has been suggested that these organic compounds were responsible for mediating the effects of DEP through their regulation of gene expression, the molecular mechanism of action of DEP has not been fully elucidated. In this study, we examined the direct effect of DEP extracts and their constituents on gene expression and phenotype in the fetal thymus. Fetal thymuses from C57BL/6 mice were exposed to DEP extracts for 24 hrs, after which their gene expression was analyzed using an Affymetrix GeneChip system. DEP extracts up-regulated several genes known as arylhydrocarbon receptor (AhR)-target genes, including cytochrome P450 1a1 (Cyp1a1), 1b1 (Cyp1b1), TCDD-inducible poly(ADP-ribose) polymerase (Tiparp), and scinderin (Scin). Similarly, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and benzo[a]pyrene (B[a]P), which are AhR ligands, induced remarkably similar changes in gene expression compared to DEP extracts. In addition, our data showed little contribution of quinones to DEP extracts-induced changes in gene expression in fetal thymus through oxidative stress responses. These changes in gene expression were also confirmed by semi-quantitative RT-PCR. Furthermore, DEP extracts skewed thymic T-cell differentiation in favor of the production of CD8 T-cells, which was also observed when exposed to AhR ligands. Our results suggest that organic compounds adsorbed onto DEP alter thymic gene expression and directly affect thymocyte development by activating the AhR.

Abstract  Fetal and early postnatal life represent critical periods in vertebrate immune system development. Disruption of such development by perinatal immunotoxic chemical exposure has been widely described in experimental animal models. The resultant inhibited postnatal immune responses in such animals are often more dramatic and persistent than those after exposure during adult life. Further, recent reports suggest that prenatal exposure to immunotoxicants may exacerbate postnatal aberrant immune responses (e.g., hypersensitivity disorders and autoimmune disease) in genetically predisposed rodents. Limited information is available regarding the possibility of inhibited postnatal immune capacity in humans as a result of developmental immunotoxicant exposure. The multifactorial nature of hypersensitivity and autoimmune responses will further complicate the elucidation of possible relationships between chemical exposure during ontogeny of the human immune system and immune-mediated disease later in life. Taken together, however, the available animal data suggest the potential for altered postnatal immune function in humans exposed to immunotoxicants (e.g., environmental chemicals and therapeutic agents) during fetal and/or early postnatal life.

Abstract  BIOSIS COPYRIGHT: BIOL ABS. Select polycyclic aromatic hydrocarbons (PAHs), their derivatives, and nicotine were measured in eight homes in Columbus, Ohio, during the winter of 1986/1987 by Chuang et al. (1988, Technical Report EPA/600/4-28/028, U.S. EPA). These homes had different indoor PAH sources, namely, environmental tobacco smoke, gas cooking/beating, and electrical cooking stoves. We use a combination of correlation analysis, factor analysis and multiple regression to identify and apportion the different sources of PAHs. We find that, of all the sources, environmental tobacco smoke appears to have the greatest impact on the total indoor PAH concentrations. In smokers' homes, more than 87% of the total PAH is due to this source. Background sources are the largest contributor to PAHs in nonsmokers' homes. We also study the source apportionment of total extractable organic material (EOM) measured in the homes. In smokers' homes, EOM can be attributed mainly to environmental tobacco smoke (49%

Abstract  Changes in phase II drug-metabolizing enzyme expression during development, as well as the balance between phase I and phase II enzymes, can significantly alter the pharmacokinetics for a given drug or toxicant. Although our knowledge is incomplete, many of the phase II enzymes are expressed early in development. There is evidence for glutathione S-transferase A1/A2 (GSTA1/A2), GSTM, and GSTP1 in fetal liver, lung and kidney, although tissue-specific patterns and changes with time are observed. N-Acetyltransferase 1 (NAT1) activity also has been reported throughout gestation in fetal liver, adrenal glands, lung, kidney, and intestine. Only postnatal changes in NAT1 expression were apparent. Nothing is known about human NAT2 developmental expression. Some UDP-glucuronosyltransferase and sulfotransferase isoforms also are detectable in fetal liver and other tissues by the first or second trimester, and substantial changes in isoform expression patterns, as well as overall expression levels, are observed with increasing maturity. Finally, expression of both epoxide hydrolases 1 and 2 (EPHX1 and EPHX2) is observed in fetal liver, and for the former, increased expression with time has been documented. Less is known about ontogenic molecular control mechanisms. Limited data suggest that the hepatocyte nuclear factor and CCAAT/enhancer binding protein families are critical for fetal liver drug-metabolizing enzyme expression whereas D element binding protein and related factors may regulate postnatal hepatic expression. There is a paucity of data regarding mechanisms for the onset of extrahepatic fetal expression or specific mechanisms determining temporal switches, such as those observed within the CYP3A and flavin-containing monooxygenase families.

Abstract  The expanded Second Edition of Dr. Rothman's acclaimed Modern Epidemiology reflects the remarkable conceptual development of this evolving science and the engagement of epidemiologists with an increasing range of current public health concerns. This landmark work is the most comprehensive and cohesive text on the principles and methods of contemporary epidemiologic research.Coauthored by two leading epidemiologists, with 15 additional contributors, the Second Edition presents a much broader range of concepts and methods than Dr. Rothman's single-authored original edition. Coverage of basic measures and study types is more thorough and includes a new chapter on field methods. New chapters on advanced topics in data analysis, such as hierarchical regression, are also included. A new section covers specific areas of research such as infectious disease epidemiology, ecologic studies, disease surveillance, analysis of vital statistics, screening, clinical epidemiology, environmental and occupational epidemiology, reproductive and perinatal epidemiology, genetic epidemiology, and nutritional epidemiology.

Abstract  The effect of ultrafine, airborne, carrier particles on the deposition, retention, and biological fate of inhaled polycyclic aromatic hydrocarbons (PAHs) was studied. Using a radiolabeled model PAH, [3H]benzo(a)pyrene ([3H]BaP), Fischer-344 rats were exposed by nose-only inhalation (30 min) to this compound, as a coating (15% by mass) on insoluble 67Ga2O3 particles or as a pure aerosol. These aerosols were produced by vapor condensation methods in a dynamic aerosol generation system. The concentrations of [3H]BaP in the coated and homogeneous aerosols were 0.6 and 1.0 μg/liter of air, respectively, while the mass median diameter of both these aerosols was approximately 0.1 μm. Pulmonary retention of 3H radioactivity was longer in animals exposed to the [3H]BaP coated on the 67Ga2O3 particles. The time required to clear 90% of the initial lung burden of 67Ga2O3-associated 3H radioactivity detected 30 min postexposure was approximately 1 day as compared to 4 hr for animals exposed to the pure [3H]BaP aerosol. Tracheal clearance of 90% of the 67Ga2O3-associated 3H radioactivity (as a fraction of the amount detected 30 min postexposure) required 1 day, while only 1.5 hr were required to clear the same percentage of 3H radioactivity from the tracheas of rats exposed to the pure [3H]BaP aerosol. The rates of clearance of this 3H material to other tissues suggested that a substantial amount of the [3H]BaP coated on 67Ga2O3 was cleared from lungs by mucociliary clearance and subsequent ingestion, whereas the majority of the pure [3H]BaP aerosol was cleared by direct absorption into blood. In both cases, the ultimate fate of the majority of the [3H]BaP and its metabolites was excretion in feces. However, clearance of the 67Ga2O3-associated [3H]BaP by ingestion may have been the cause for the higher levels and longer retention times of 3H radioactivity in stomach, liver, and kidneys when compared to the levels found in these same tissues from animals exposed to the pure [3H]BaP aerosol. Thus, particle association of BaP not only increased the respiratory tract retention of this PAH, but also increased the dose of this compound and its metabolites to stomach, liver, and kidneys.

Abstract  In a continuing review of long-term toxicology and carcinogenesis studies in rats and mice, the National Toxicology Program (NTP) is confronted with many problems concerning the interpretation of tumor data. A frequently raised question is: "Should certain neoplasms be combined for overall assessment of rodent carcinogenesis data?" NTP policy is that certain neoplasms may be combined for statistical assessment of tumor data and that hyperplastic responses may be used as supportive evidence. The primary reason for combining neoplastic lesions is to gain more insight into the evidence of the carcinogenicity of a given chemical in that species of animal. This report gives the rationale, criteria, and guidelines used by the NTP for combining neoplasms for the evaluation of long-term rodent toxicology and carcinogenesis studies. The guidelines are based mainly on lesions occurring in the F344/N inbred rat and (C57BL/6 X C3H)F1 mouse and may or may not be appropriate for other strains or species. The concepts of combining neoplasms and sites should be viewed in terms of the study as a whole, since tumor formation is only one of many responses caused by chemicals in mammals. The resulting information becomes part of the "weight of the evidence" for estimating the potential hazard of a given chemical.

Abstract  Dose-response relationships for different dosages per administration of a suspension of benzo[a]pyrene (BP) and ferric oxide given intratracheally to Syrian golden hamsters were examined for respiratory carcinogenesis. Each group received 30 weekly instillations. The amounts of BP were 2.0, 1.0, 0.5, and 0.25 mg/dose, all with an equal amount of ferric oxide. A positive correlation was demonstrated between the dose level of individual administrations and the yield of respiratory tumors. Both tumor latency and tumor multiplicity were related to the dose per administration and hence total dose. As previously noted in this animal model, squamous cell carcinomas were the predominant morphologic type, and the most frequently affected site was the bronchi, followed by the trachea. © 1972, Oxford University Press.

Abstract  The effects of benzo(a)pyrene (50328) (BP) on fertility, and on developing embryos were studied in mice. In 10 experiments, female White-Swiss-mice were fed 0.25, 0.5, or 1.0 milligrams (mg) BP per gram of food before mating, during pregnancy, during lactation, or after weaning. Male mice were fed 0.25mg per gram of food prior to mating. Some pregnant mice were sacrificed and fetuses observed for fluorescence; some tissues were extracted, sectioned, and scanned with a spectrophotometer. In experiment one, only one mouse fed 1.0mg BP delivered. In experiment two, 1.0mg BP fed for 20 days before mating did not affect fertility. In experiment three, weight gain per mouse was less in those whose mothers received 1.0mg BP than in controls. In experiment four, four remaining young (five were eaten) of a mother fed 0.25mg BP failed to gain weight. In experiment five, weaned mice fed 0.25mg BP failed to gain weight equal to those fed pellets without BP. In experiment six, 1.0mg BP fed to four weaned mice had no effect on weight gain. In experiment seven, mice ate some pellets containing 0.25mg BP, but few ate pellets containing 0.5 or 1.0mg BP. In experiment eight, 0.25, 0.5, and 1.0mg BP fed prior to mating did not affect female fertility. In experiment nine, male mice fed 0.25mg BP had decreased fertility. In experiment ten, four of five adult females had viscera with blue flourescence, and two kidneys of these four were positive for BP. In general, BP was found in kidneys but not in embryos. Mice fed BP after being fed standard pellet decreased in weight dependent on dose, while mice fed BP in maximum dose from weaning gained weight. Cannibalism was frequent at higher doses. No injury to embryos or fertility was observed. No malformations or resorption of embryos were observed. No deaths were observed from BP administration. The authors conclude that BP is not toxic at the administered doses.

Abstract  This study was conducted to investigate whether bitumen fumes should be considered carcinogenic to human beings. A historical cohort of heavily exposed mastic asphalt workers was followed from 1959 through 1984 (inclusive) with regard to cancer incidence. A total of 679 Danish men were included in the study cohort. Among these, 75 new cases of cancer were observed within the period studied. The cancer incidence observed among the group significantly exceeded that of the total Danish male population, the standardized morbidity ratio (SMR) being 195 (95% confidence interval (95% CI) 153-244). Significant increases were seen for cancer of the mouth (SMR 1111, 95% CI 135-4014), the esophagus (SMR 698, 95% CI 144-2039), the rectum (SMR 318, 95% CI 128-656), and the lung (SMR 344, 95% CI 227-501). It is suggested that exposure to cracking products in the fumes of heated bitumen has contributed to the elevated cancer incidence observed.

Abstract  The penetration of benzo[a]pyrene (BaP) through a nonbiological experimental model of the bronchial lining layer (BLL) was studied. The purpose was to investigate how the lipid-aqueous structure of the BLL might influence the rate of penetration of polycyclic aromatic hydrocarbons (PAHs) from the ambient air to the bronchial epithelium. The experimental model was built up in a petri dish by (A) a thin layer of paraffin at the bottom, simulating the lipophilic membranes of the epithelial cells; (B) an aqueous starch gel on top of the paraffin, simulating the viscous aqueous region of the BLL; and (C) a thin layer of phosphatidylcholine, simulating the surfactant lipid layer at the air interface. BaP was administered on top of the barrier either diffusely or from a point source, and the penetration was studied by measuring the concentration of BaP as a function of time both in the liquid phase and in the paraffin. Comparisons were made with a purely aqueous barrier without the thin phospholipid layer. The results show that the rate of penetration of BaP through the purely aqueous barrier is orders of magnitude higher than that of the lipid-aqueous barrier. A thin layer of phospholipids at the air interface thus has a tremendous influence on the rate of penetration of lipophilic substances and probably this, rather than the release rate of PAHs from their carrier particles, is the rate-determining step in the overall transport of PAHs from such particles to the bronchial epithelium.

Abstract  The Report on Carcinogens (RoC) is an informational scienti.c and public health document that identifies and discusses agents, substances, mixtures, or exposure circumstances (hereinafter referred to as substances) that may pose a hazard to human health by virtue of their carcinogenicity. For each listed substance, the RoC contains a substance profile which provides information on (1) the listing status, (2) cancer studies in humans and animals, (3) studies of genotoxicity (ability to damage genes) and biologic mechanisms, (4) the potential for human exposure to these substances, and (5) Federal regulations to limit exposures. The RoC does not present quantitative assessments of the risks of cancer associated with these substances. Thus, the listing of substances in the RoC only indicates a potential hazard and does not establish the exposure conditions that would pose cancer risks to individuals in their daily lives.

Abstract  Mechanism of lipid peroxidation triggered by vanadium in human term placental microsomes was reinvestigated in vitro. Production of lipid peroxyl radicals was estimated from co-oxygenation of benzo(a)pyrene and benzo(a)pyrene-7,8-dihydrodiol. Vanadyl(IV), but not vanadate(V) caused a dose-dependent co-oxygenation. Vanadate(V) required the presence of reduced nicotinamide adenine dinucleotide phosphate to trigger co-oxygenation of benzo(a)pyrene-7,8-dihydrodiol. To determine the role of pre-formed lipid hydroperoxides, the results obtained with partially peroxidized linoleic acid were compared with those of fresh linoleate. Superoxide dismutase inhibited the co-oxygenation of reaction when fresh linoleic acid was used. To further characterize the role of superoxide anion-radical in the vanadium redox cycling, the increase of optical density of vanadate(V) dissolved in Tris buffer was measured at 328 nm during the addition of KO2. The rate of this reaction producing peroxy-vanadyl complex was decreased by superoxide dismutase, especially, in the presence of catalase. It is suggested that vanadium catalyzes two separate processes, both leading to enhanced lipid peroxidation: (i) initiation, dependent on superoxide and triggered by peroxy-vanadyl; (ii) propagation, dependent on pre-formed lipid hydroperoxide not sensitive to superoxide dismutase. It is postulated that the vanadium-triggered initiation of lipid peroxidation may be crucial for toxicity in organs with limited endogenous lipid peroxidation.