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N Rothman

Publications and source records attributed to N Rothman.

At least 55 records · Page 3Linked to original sources
PubMed1999

Occupational cancer epidemiology in the coming decades.

Occupational studies have identified many of the established chemical carcinogens. Studies in the next millennium will be needed to identify the hazardous agents in occupations known to have high cancer rates, to assess human risks from animal carcinogens that have not been well evaluated epidemiologically, to provide information on women and minorities, to evaluate interactions with genetic factors and other risk factors, to contribute to our understanding of risks from the spread of chemicals from the workplace to the general environment, and to identify mechanisms of cancer. The traditional retrospective cohort design will be insufficient to meet these needs. Population-based case-control, nested case-control, prospective cohorts, and cross-sectional designs will assume more important roles because of the need to collect information on nonoccupational risk factors and biological tissues. Improvement in the assessment of quantitative exposures is needed for the efficient evaluation of interactions between occupational exposures, genetic factors, and nonoccupational exposures.

Carcinogens↗
PubMed1999

The impact of misclassification in case-control studies of gene-environment interactions.

In this chapter we describe the impact of risk factor misclassification in case-control studies designed to estimate gene-environment interactions. We show that under certain scenarios even small amounts of exposure or genotype misclassification can substantially attenuate the interaction effect and, as a consequence, dramatically increase the sample size required to study these interactions. A consideration of how sample size is affected by exposure and genotype misclassification in the study design phase should help to identify situations where obtaining better risk factor information is crucial for the feasibility of studies.

Case-Control Studies↗
PubMed1999

Misclassification in case-control studies of gene-environment interactions: assessment of bias and sample size.

In studies of gene-environment interactions, exposure misclassification can lead to bias in the estimation of an interaction effect and increased sample size. The magnitude of the bias and the consequent increase in sample size for fixed misclassification probabilities are highly dependent on the prevalence of the misclassified factor and on the interaction model. This paper describes a relatively simple approach to assess the impact of misclassification on bias in the estimation of multiplicative or additive interactions and on sample size requirements. Applications of this method illustrate that even small errors in the assessment of environmental or genetic factors can result in biased interaction parameters and substantially increased sample size requirements that can compromise the feasibility of the study. Also, an example is provided where nondifferential misclassification biases an additive interaction parameter away from the null value, even under conditions where a multiplicative interaction parameter will always be biased toward the null value. Efforts to improve the accuracy in measuring both genetic and environmental factors are critical for the valid assessment of gene-environment interactions in case-control studies.

Benzo(a)pyrene↗
PubMed1999

Benzene increases aneuploidy in the lymphocytes of exposed workers: a comparison of data obtained by fluorescence in situ hybridization in interphase and metaphase cells.

Benzene is an established human leukemogen that increases the level of chromosome aberrations in lymphocytes of exposed workers. Numerical aberrations (aneusomy) can be observed by fluorescence in situ hybridization (FISH) in both interphase and metaphase cells. Whereas interphase FISH allows nondividing cells to be analyzed, one advantage of metaphase FISH is that it can also detect structural changes. The present study compares the abilities of metaphase and interphase FISH to detect aneusomy of chromosomes 7 and 8 in healthy benzene-exposed human subjects. Metaphase and interphase cells from the peripheral blood of 43 workers exposed to benzene (median = 31 ppm, 8-hr TWA) and 44 frequency-matched controls were analyzed by FISH. Normal diploid cells contained two hybridization signals, whereas those that were potentially monosomic contained one, trisomic 3 and tetrasomic 4. The frequency of cells with one hybridization signal for chromosome 7 in metaphase spreads rose from 2.72 +/- 0.19 (%, mean +/- SE) in controls to 3.79 +/- 0.63 in workers exposed to 31 or fewer ppm benzene and 5.9 +/- 0.85 in those exposed to more than 31 ppm (P(trend) < 0.0001). No similar dose-dependent increase in the frequency of cells with one hybridization signal was observed by interphase FISH, probably because of probe overlap artifact. Although significant dose-dependent increases in the frequency of cells with three hybridization signals for chromosome 7 were detected by both methods in the higher-exposed group, a larger, more significant difference was detected by metaphase FISH between controls and workers exposed to 31 or fewer ppm. Similar data were obtained for chromosome 8. Interphase and metaphase FISH were moderately correlated for three hybridization signals but not for one hybridization signal in chromosome 7 or 8. In general, metaphase FISH was more sensitive in detecting both monosomy and trisomy in the lymphocytes of exposed workers.

Adult↗
PubMed1998

Increased translocations and aneusomy in chromosomes 8 and 21 among workers exposed to benzene.

Chromosome aberrations in peripheral blood lymphocytes have been used for many years to monitor human populations exposed to potential carcinogens. Recent reports have confirmed the validity of this approach by demonstrating that elevated levels of chromosome aberrations in lymphocytes are associated with subsequent increased cancer risk, especially for increased mortality from hematological malignancies including acute myeloid leukemia (AML). We postulated that this approach could be improved in two ways: (a) by detecting oncogenic disease-specific aberrations; and (b) by using chromosome painting so that many more metaphases could be analyzed. Numerical and structural aberrations in chromosomes 8 and 21 are commonly observed in AML. In the present study, we painted chromosomes 8 and 21 in lymphocyte metaphases from 43 healthy workers exposed to benzene, an established cause of AML, and from 44 matched controls. To examine dose-response relationships the workers were divided into two groups at the median exposure level, a lower-exposed group (< or = 31 ppm; n = 21), and a higher-exposed group (> 31 ppm; n = 22). Benzene exposure was associated with significant increases in hyperdiploidy of chromosomes 8 (1.2, 1.5, and 2.4 per 100 metaphases; P < 0.0001) and 21 (0.9, 1.1, and 1.9 per 100 metaphases; P < 0.0001). Translocations between chromosomes 8 and 21 were increased up to 15-fold in highly exposed workers (0.01, 0.04, and 0.16 per 100 metaphases; P < 0.0001). In one highly exposed individual, these translocations were reciprocal and were detectable by reverse transcriptase-PCR. These data indicate a potential role for t(8;21) in benzene-induced leukemogenesis and are consistent with the hypothesis that detection of specific chromosome aberrations may be a powerful approach to identify populations at increased risk of leukemia.

Acute Disease↗
PubMed1998

Heterocyclic amine content of pork products cooked by different methods and to varying degrees of doneness.

Heterocyclic amines (HCAs) are known mutagens and animal carcinogens produced in meats cooked at high temperature. As pork is the second most frequently consumed meat in the United States, five predominant HCAs [2-amino-3-methylimidazo[4,5-f]quinoline (IQ), 2-amino-3,4-dimethylimidazo[4,5-f]quinoline (MeIQ), 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), 2-amino-3,4,8-trimethylimidazo[4.5-f]quinoxaline (DiMeIQx) and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP)] were measured in various pork products, cooked by different techniques and to varying doneness levels. Pork chops and ham slices were pan-fried and oven-broiled; bacon was pan-fried, oven-broiled or microwaved; hot dogs were pan-fried, oven-broiled, grilled/barbecued or boiled; sausage links and patties were pan-fried. All the products were cooked to three levels of doneness: just until done, well done or very well done. HCA type and level varied substantially by pork product, cooking method and doneness level. The highest PhIP levels were found in well done and very well done oven-broiled bacon; for very well done 30.3 and 4.0 ng per gram of meat of PhIP and MeIQx, respectively. Pan-fried very well done sausage patties contained 5.4 ng of MeIQx per gram of meat, while sausage links contained 1.3 ng per gram of meat. MeIQx was formed in well done and very well done pan-fried but not broiled pork chops. Hot dogs or ham slices had low or undetectable levels of HCAs. These results demonstrate that epidemiological studies investigating the relationship between HCA intake and cancer risk need to incorporate type of meat, cooking method and degree of doneness/surface browning into questions to assess adequately an individual's HCA exposure.

Animals↗
PubMed1998

Heterocyclic amine content in beef cooked by different methods to varying degrees of doneness and gravy made from meat drippings.

Meats cooked at high temperatures sometimes contain heterocyclic amines (HCAs) that are known mutagens and animal carcinogens, but their carcinogenic potential in humans has not been established. To investigate the association between HCAs and cancer, sources of exposure to these compounds need to be determined. Beef is the most frequently consumed meat in the United States and for this study we determined HCA values in beef samples cooked in ways to represent US cooking practices, the results of which can be used in epidemiological studies to estimate HCA exposure from dietary questionnaires. We measured five HCAs [2-amino-3-methylimidazo[4,5-f]quinoline (IQ), 2-amino-3,4-dimethylimidazo[4,5-f]quinoline (MeIQ), 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), 2-amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline (DiMeIQx) and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP)] in different types of cooked beef using solid-phase extraction and HPLC. Steak and hamburger patties were pan-fried, oven-broiled, and grilled/barbecued to four levels of doneness (rare, medium, well done or very well done), while beef roasts were oven cooked to three levels of doneness (rare, medium or well done). The measured values of the specific HCAs varied with the cut of beef, cooking method, and doneness level. In general, MeIQx content increased with doneness under each cooking condition for steak and hamburger patties, up to 8.2 ng/g. PhIP was the predominant HCA produced in steak (1.9 to 30 ng/g), but was formed only in very well done fried or grilled hamburger. DiMeIQx was found in trace levels in pan-fried steaks only, while IQ and MeIQ were not detectable in any of the samples. Roast beef did not contain any of the HCAs, but the gravy made from the drippings from well done roasts had 2 ng/g of PhIP and 7 ng/g of MeIQx. Epidemiological studies need to consider the type of meat, cooking method and degree of doneness/surface browning in survey questions to adequately assess an individual's exposure to HCAs.

Animals↗
PubMed1998

Serum concentrations of organochlorine compounds and endometrial cancer risk (United States).

OBJECTIVES: Endogenous and exogenous estrogens are important in the development of endometrial cancer. Several organochlorine compounds, such as o,p'-DDT, have estrogenic properties. The objective of this case-control analysis was to examine serum concentrations of organochlorine compounds and risk of endometrial cancer. METHODS: Analyses were based on a sample of 90 endometrial cancer cases and 90 individually matched community controls from a multicenter case-control study in five geographic regions of the United States. Information on potential confounders, including menstrual and reproductive factors, cigarette smoking, diet, and weight, was obtained by interview. RESULTS: The adjusted relative risk of endometrial cancer in the highest quartile of exposure compared with women in the lowest quartile was 0.7 (95 percent confidence interval [CI] = 0.2-2.0) for p,p'-DDE, and 0.9 for total polychlorinated biphenyls (PCBs) (CI = 0.4-2.5). CONCLUSIONS: These findings do not support the hypothesis that organochlorine compounds are linked to the development of endometrial cancer.

Adolescent↗
PubMed1998

Increased aneusomy and long arm deletion of chromosomes 5 and 7 in the lymphocytes of Chinese workers exposed to benzene.

Two of the most common cytogenetic changes in therapy- and chemical-related leukemia are the loss and long (q) arm deletion of chromosomes 5 and 7. The detection of these aberrations in lymphocytes of individuals exposed to potential leukemogens may serve as useful biomarkers of increased leukemia risk. We have used a novel fluorescence in situ hybridization (FISH) procedure to determine if specific aberrations in chromosomes 1, 5 and 7 occur at an elevated rate in the blood cells of workers exposed to benzene. Forty-three healthy workers exposed to a wide range of benzene concentrations (median 31 p.p.m., 8 h time-weighted average) and 44 unexposed controls from Shanghai were studied. Whole blood was cultured and metaphase spreads were harvested at 72 h. Benzene exposure was associated with increases in the rates of monosomy 5 and 7 but not monosomy 1 (P < 0.001, P < 0.0001 and P = 0.94, respectively) and with increases in trisomy and tetrasomy frequencies of all three chromosomes. Long arm deletion of chromosomes 5 and 7 was increased in a dose-dependent fashion (P = 0.014 and P < 0.0001) up to 3.5-fold in the exposed workers. These results demonstrate that leukemia-specific changes in chromosomes 5 and 7 can be detected by FISH in the peripheral blood of otherwise healthy benzene-exposed workers. We suggest that aberrations in chromosomes 5 and 7 may be useful biomarkers of early biological effect for benzene exposure.

Adult↗
PubMed1998

Hemoglobin and albumin adducts of benzene oxide among workers exposed to high levels of benzene.

Benzene oxide (BO) reacts with cysteinyl residues in hemoglobin (Hb) and albumin (Alb) to form protein adducts (BO-Hb and BO-Alb), which are presumed to be specific biomarkers of exposure to benzene. We analyzed BO-Hb in 43 exposed workers and 42 unexposed controls, and BO-Alb in a subsample consisting of 19 workers and 19 controls from Shanghai, China, as part of a larger cross-sectional study of benzene biomarkers. The adducts were analyzed by gas chromatography-mass spectrometry following reaction of the protein with trifluoroacetic anhydride and methanesulfonic acid. When subjects were divided into controls (n = 42) and workers exposed to < or =31 (n = 21) and >31 p.p.m. (n = 22) benzene, median BO-Hb levels were 32.0, 46.7 and 129 pmol/g globin, respectively (correlation with exposure: Spearman r = 0.67, P < 0.0001). To our knowledge, these results represent the first observation in humans that BO-Hb levels are significantly correlated with benzene exposure. Median BO-Alb levels in these 3 groups were 103 (n = 19), 351 (n = 7) and 2010 (n = 12) pmol/g Alb, respectively, also reflecting a significant correlation with exposure (Spearman r = 0.90, P < 0.0001). The blood dose of BO predicted from both Hb and Alb adducts was very similar. These results clearly affirm the use of both Hb and Alb adducts of BO as biomarkers of exposure to high levels of benzene. As part of our investigation of the background levels of BO-Hb and BO-Alb found in unexposed persons, we analyzed recombinant human Hb and Alb for BO adducts. Significant levels of both BO-Hb (19.7 pmol/g) and BO-Alb (41.9 pmol/g) were detected, suggesting that portions of the observed background adducts reflect an artifact of the assay, while other portions are indicative of either unknown exposures or endogenous production of adducts.

Benzene↗
PubMed1998

Urinary excretion of phenol, catechol, hydroquinone, and muconic acid by workers occupationally exposed to benzene.

OBJECTIVES: Animal inhalation studies and theoretical models suggest that the pattern of formation of benzene metabolites changes as exposure to benzene increases. To determine if this occurs in humans, benzene metabolites in urine samples collected as part of a cross sectional study of occupationally exposed workers in Shanghai, China were measured. METHODS: With organic vapour monitoring badges, 38 subjects were monitored during their full workshift for inhalation exposure to benzene. The benzene urinary metabolites phenol, catechol, hydroquinone, and muconic acid were measured with an isotope dilution gas chromatography mass spectroscopy assay and strongly correlated with concentrations of benzene air. For the subgroup of workers (n = 27) with urinary phenol > 50 ng/g creatinine (above which phenol is considered to be a specific indicator of exposure to benzene), concentrations of each of the four metabolites were calculated as a ratio of the sum of the concentrations of all four metabolites (total metabolites) and were compared in workers exposed to > 25 ppm v < or = 25 ppm. RESULTS: The median, 8 hour time weighted average exposure to benzene was 25 ppm. Relative to the lower exposed workers, the ratio of phenol and catechol to total metabolites increased by 6.0% (p = 0.04) and 22.2% (p = 0.007), respectively, in the more highly exposed workers. By contrast, the ratio of hydroquinone and muconic acid to total metabolites decreased by 18.8% (p = 0.04) and 26.7% (p = 0.006), respectively. Similar patterns were found when metabolite ratios were analysed as a function of internal benzene dose (defined as total urinary benzene metabolites), although catechol showed a more complex, quadratic relation with increasing dose. CONCLUSIONS: These results, which are consistent with previous animal studies, show that the relative production of benzene metabolites is a function of exposure level. If the toxic benzene metabolites are assumed to be derived from hydroquinone, ring opened products, or both, these results suggests that the risk for adverse health outcomes due to exposure to benzene may have a supralinear relation with external dose, and that linear extrapolation of the toxic effects of benzene in highly exposed workers to lower levels of exposure may underestimate risk.

Air Pollutants, Occupational↗
PubMed1998

Biomonitoring of United States Army soldiers serving in Kuwait in 1991.

Biomarkers of polycyclic aromatic hydrocarbon (PAH) exposure and genetic biomarkers of potential cancer susceptibility were determined in a group of United States Army soldiers who were deployed to Kuwait and Saudi Arabia in 1991 in the aftermath of the Persian Gulf War. Because hundreds of oil well fires were still burning, there was concern that ground troops stationed in Kuwait might be exposed to high levels of PAHs and other toxicants. The United States Army Environmental Hygiene Agency monitored air and soil for ambient PAHs. In addition, a group of 61 soldiers was involved in the biomonitoring study reported here. These soldiers kept diaries of daily activities and provided blood and urine samples in Germany (June) before deployment to Kuwait, after 8 weeks in Kuwait (August), and 1 month after the return to Germany (October). Here we present data for PAH-DNA adducts measured by immunoassay in blood cell DNA samples obtained at all three sampling times from 22 soldiers and bulky aromatic adducts measured by 32P-postlabeling in blood cell DNA samples from 20 of the same soldiers. Urinary 1-hydroxypyrene-glucuronide levels were determined by synchronous fluorescence spectrometry in a matched set of samples from 33 soldiers. Contrary to expectations, environmental monitoring showed low ambient PAH levels in the areas where these soldiers were working in Kuwait. For both DNA adduct assays, levels were the lowest in Kuwait in August and increased significantly after the soldiers returned to Germany (October). Urinary 1-hydroxypyrene-glucuronide levels were also lowest in Kuwait and highest in Germany, but the differences were not statistically significant. The PAH-exposure biomarker levels were not significantly influenced by polymorphic variations of CYP1A1 (MspI) and glutathione S-transferases M1 and T1. Overall, the data suggest that this group of soldiers was not exposed to elevated levels of PAHs while deployed in Kuwait.

DNA Primers↗
PubMed1997

Validation of benzene exposure assessment.

We conducted a methodologic study to validate a quantitative retrospective exposure assessment method used in a follow-up study of workers exposed to benzene. Assessment of exposure to benzene was carried out in 672 factories in 12 cities in China. Historical exposure data were collected for 3179 unique job titles. The basic unit for exposure assessment was a factory/work-unit/job-title combination over seven periods between 1949 and 1987. A total of 18,435 exposure estimates was developed, using all available historical information, including 8477 monitoring data. Overall, 38% of the estimates were based on benzene monitoring data. The highest time-weighted average exposures occurred in the rubber industry (30.7 ppm), particularly for rubber glue applicators (52.6 ppm). Because of its recognized link with benzene exposure, the association between a clinical diagnosis of benzene poisoning (hematotoxicity) and benzene exposure was evaluated (412 cases and 614,509 person-years) to validate the exposure-assessment method. Relative risks of benzene hematotoxicity increased very sharply with increasing estimated intensity of benzene exposure. Odds ratios were 2.2 (95% CI: 1.7-2.9), 4.7 (95% CI: 3.4-6.5), and 7.2 (95% CI: 5.3-9.8) for the intensity levels of less than 5 ppm, 5-19 ppm, 20-39 ppm, and 40 and more ppm, respectively. This sharp trend between benzene hematotoxicity and estimated exposure to benzene indicated that the exposure-estimation method used in this cancer epidemiology study is reliable.

Benzene↗
PubMed1997

Benzidine-DNA adduct levels in human peripheral white blood cells significantly correlate with levels in exfoliated urothelial cells.

In a cross-sectional study of 33 workers exposed to benzidine and benzidine dyes and 15 non-exposed controls, we previously reported that exposure status and internal dose of benzidine metabolites were strongly correlated with the levels of specific benzidine-DNA adducts in exfoliated urothelial cells. We also evaluated DNA adduct levels in peripheral white blood cells (WBC) of a subset of 18 exposed workers and 7 controls selected to represent a wide range of adducts in exfoliated urothelial cells. Samples were coded and then DNA was analyzed using 32P-postlabeling, along with n-butanol extraction. One adduct, which co-chromatographed with a synthetic N-(3'-phospho-deoxyguanosin-8-yl)-N'-acetylbenzidine standard, predominated in those samples with adducts present. The median level (range) of this adduct in WBC DNA was 194.4 (3.2-975) RAL x 10(9) in exposed workers and 1.4 (0.1-6.4) in the control subjects (p = 0.0002, Wilcoxon Rank Sum Test). There was a striking correlation between WBC and exfoliated urothelial cell adduct levels (Pearson r = 0.84, p < 0.001) among exposed subjects. In addition, the sum of urinary benzidine, N-acetylbenzidine and N,N'-diacetylbenzidine correlated with the levels of this adduct in both tissues. This is the first study in humans to show a relationship for a specific carcinogen adduct in a surrogate tissue and in urothelial cells, the target for urinary bladder cancer.

Adult↗
PubMed1997

A nested case-control study of non-Hodgkin lymphoma and serum organochlorine residues.

BACKGROUND: The steady worldwide increase in the incidence of non-Hodgkin lymphoma during the past few decades remains mostly unexplained. Several studies suggest that there may be an association between the agricultural use of the organochlorine 1,1,1-trichloro-2,2'bis(p-chlorophenyl)ethane (DDT) and increased risk of non-Hodgkin lymphoma. We have investigated the association between risk of non-Hodgkin lymphoma and body burden of selected organochlorines in the general population in a nested case-control study. METHODS: We measured prediagnostic serum concentrations of DDT, its metabolites, and other organochlorines, including polychlorinated biphenyls (PCBs), in 74 cases of non-Hodgkin lymphoma and 147 matched controls identified from a prospective cohort of 25,802 adults, established in 1974 in Washington County, Maryland, USA. We report results for total lipid-corrected serum concentrations of DDT and total PCBs. FINDINGS: There was a strong dose-response relation between quartiles of total lipid-corrected serum PCB concentrations and risk of non-Hodgkin lymphoma overall (odds ratios by quartile: 1.0; 1.3 [95% CI 0.5-3.3]; 2.8 [1.1-7.6]); and 4.5 [1.7-12.0]; p for trend = 0.0008) and separately in men and in women. There was also evidence suggesting that seropositivity for the Epstein-Barr virus early antigen potentiated the effects of serum PCBs. By contrast, total lipid-corrected serum concentrations of DDT were not associated with risk of non-Hodgkin lymphoma. INTERPRETATION: These results should be regarded as hypothesis-generating. Before causal inferences can be made about exposure to PCBs and increased risk of non-Hodgkin lymphoma, our findings require replication and the biological plausibility of the association needs further investigation.

Adult↗
PubMed1997

Benzene and the dose-related incidence of hematologic neoplasms in China. Chinese Academy of Preventive Medicine--National Cancer Institute Benzene Study Group.

BACKGROUND: Benzene is a widely distributed environmental contaminant known to cause leukemia, particularly acute nonlymphocytic leukemia, and perhaps other hematologic neoplasms and disorders. Few epidemiologic studies, however, have been able to address relationships between the extent of benzene exposure and the level of risk. PURPOSE: A large cohort study was carried out in China to evaluate the risks of developing specific hematologic neoplasms and selected related disorders in relationship to quantitative estimates of occupational benzene exposure. METHODS: A cohort of 74828 benzene-exposed and 35805 unexposed workers employed from 1972 through 1987 in 12 cities in China was identified and followed to determine the incidence of hematologic neoplasms and related disorders. Estimates of benzene exposure were derived from work histories and available historic benzene measurements. Existing pathologic material and supporting medical records were reviewed to establish diagnoses of disease. Relative risks (RRs) (i.e., ratios of incidence rates for specific hematologic neoplasms and related disorders in the benzene-exposed group to incidence rates in the unexposed group) were determined by use of Poisson regression analysis, with stratification by age and sex. RESULTS: For workers historically exposed to benzene at average levels of less than 10 parts per million (ppm), the RR for all hematologic neoplasm combined was 2.2 (95% confidence interval [CI] = 1.1-4.2), and, for the combination of acute nonlymphocytic leukemia and related myelodysplastic syndromes, the RR was 3.2 (95% CI = 1.0-10.1). For individuals who were occupationally exposed to benzene at constant levels of 25 ppm or more, the RR for the combination of acute nonlymphocytic leukemia and related myelodysplastic syndromes was 7.1 (95% CI = 2.1-23.7). Workers with 10 or more years of benzene exposure had an RR of developing non-Hodgkin's lymphoma of 4.2 (95% CI = 1.1-15.9), and the development of this neoplasm was linked most strongly to exposure that had occurred at least 10 years before diagnosis (i.e., distant exposure) (P for trend = .005, two-sided). In contrast, the risk for the combination of acute nonlymphocytic leukemia and related myelodysplastic syndromes was significantly increased among those with more recent benzene exposure (P for trend = .003, two-sided), but it was not linked to distant exposure (P for trend = .51, two-sided). CONCLUSIONS: The results of this study suggest that benzene exposure is associated with a spectrum of hematologic neoplasms and related disorders in humans. Risks for these conditions are elevated at average benzene-exposure levels of less than 10 ppm and show a tendency, although not a strong one, to rise with increasing levels of exposure. The temporal pattern of benzene exposure appears to be important in determining the risk of developing specific diseases.

Age Distribution↗
PubMed1997

Benzene poisoning, a risk factor for hematological malignancy, is associated with the NQO1 609C-->T mutation and rapid fractional excretion of chlorzoxazone.

Benzene is a ubiquitous occupational hematotoxin and leukemogen, but people vary in their response to this toxic agent. To evaluate the impact of interindividual variation in enzymes that activate (i.e., CYP2E1) and detoxify (i.e., NQO1) benzene and its metabolites, we carried out a case-control study in Shanghai, China, of occupational benzene poisoning (BP; i.e., hematotoxicity), which we show is itself strongly associated with subsequent development of acute nonlymphocytic leukemia and the related myelodysplastic syndromes (relative risk, 70.6; 95% confidence interval, 11.4-439.3). CYP2E1 and NQO1 genotypes were determined by PCR-RFLP, and CYP2E1 enzymatic activity was estimated by the fractional excretion of chlorzoxazone (fe(6-OH)) for 50 cases of BP and 50 controls. Subjects with both a rapid fe(6-OH). and two copies of the NQO1 609C-->T mutation had a 7.6-fold (95% confidence interval, 1.8-31.2) increased risk of BP compared to subjects with a slow fe(6-OH) who carried one or two wild-type NQO1 alleles. In contrast, the CYP2E1 PstI/RsaI polymorphism did not influence BP risk. This is the first report that provides evidence of human susceptibility to benzene-related disease. Further evaluation of susceptibility for hematotoxicity and hematological malignancy among workers with a history of occupational exposure to benzene is warranted.

Benzene↗