Abstract  To examine the concordance of two microbial genotoxicity short-term assays, 330 experimental results for the SOS chromotest using tester strain Escherichia coli PQ37 were compared with the results of the Salmonella/mammalian microsome mutagenicity assay with Salmonella typhimurium TA97, TA98, TA100, TA102, TA104, TA1535, TA1537 and/or TA1538. With respect to qualitative features, the concordance between SOS chromotest and Salmonella mutagenicity test results was 86.4% (sensitivity, 78.6%; specificity, 100%; {chi}2 = 188.6). None of the non-mutagens (N = 120) were able to induce the SOS system. Additionally, 45 of the 210 S.typhimurium mutagens (21.5%) did not induce the SOS repair system. On closer examination, the majority of these 45 compounds (84%) were mutagens with activities between 0.001 and 10 rev/nmol. Even though the experimental protocols of both systems were not standardized, the correlation coefficient for the experimental results of the two test systems was 0.7 for the 330 chemicals. Except for aliphatic epoxides (r = 0.47), the mutagenicity/SOS induction correlations for congeneric data sets (polycyclic aromatic hydrocarbons, nitroarenes, nitroarenofurans, mycotoxins) were even better (r = 0.72–0.95). Additionally, computer automated structure evaluation (CASE) analyses of the nature of the structural determinants associated with each endpoint indicate extensive homologies. The data can be taken to indicate that the two phenomena reflect common mechanisms of action.

Abstract  BIOSIS COPYRIGHT: BIOL ABS. RRM REVIEW HUMAN MONOOXYGENASE

Abstract  BIOSIS COPYRIGHT: BIOL ABS. The transformability of trihalomethanes, carbon tetrachloride, 1,1,1-trichloroethane, 1,2-dibromomethane, tetrachloroethylene, dibromochloropropane, and chlorinated benzenes was evaluated by a biofilm utilizing a mixture of primary electron acceptors (oxygen, nitrate, and sulfate). These compounds at concentrations commonly found in groundwater were continuously administered for 4 years to a biofilm column reactor that resembled polluted groundwater environments. Acetate was the primary substrate to support microbial growth. Sequential biofilm zones of aerobic respiration, denitrification, and sulfate reduction developed within the column. Transformation of the halogenated aliphatic compounds coincided with the onset of sulfate reduction in the column. The temporary absence of nitrate and sulfate in the column feed decreased the steady-state removals for several of the halogenated aliphatic compounds. These results suggest that sulfate was an important primary electron

Abstract  Rate constants for reactions of the hydroxyl radical with 25 potential organic drinking water contaminants, including solvents, haloalkanes, esters, aromatics, and pesticides for example, aldicarb, atrazine, 1,2-dibromo-3-chloropropane, endrin, glyphosate, haloforms, lindane, picloram, etc.), have been measured in water using relative rate methods. A variety of HO.-generating techniques were used, including ozone decomposition, Fenton's reaction, and a convenient new method employing photo-Fenton's s chemistry. In addition, rate constants for 19 other compounds were estimated using structure-activity relationships. The present results are consistent with previous work that demonstrated that HO. is a relatively nonselective radical toward C-H bonds, but is least reactive with aliphatic polyhalogenated compounds. Olefins and aromatics all react at nearly diffusion-controlled rates in water, unlike the case in the gas phase where these compounds react more selectively. The rate constants are useful in estimating HO.-induced oxidation rates of organic compounds in a variety of aqueous systems including atmospheric water droplets, sunlit surface waters, supercritical and near-critical water reactors, and room temperature radical oxidation processes.

Abstract  Numerous environmental contaminants can affect the developing embryo, fetus, or infant. This essay explores such questions as these: What is the importance in mutagenesis and teratogenesis of macroenvironmental pollutants such as the heavy metals, dioxin derivatives, polychlorinated diphenyl compounds, and pesticides? What is the significance of microenvironmental pollutants (or social environmental factors) such as tobacco smoke, alcohol, and pharmacologic agents over which exposed individuals have considerable control? What are some of the ethical and legal implications of these toxins of which clinicians should be aware?

Abstract  Testicular cells prepared from human organ transplant donors or from Wistar rats were used to compare 15 known reproductive toxicants with respect to their ability to induce DNA damage, measured as single-strand DNA breaks and alkali labile sites (ssDNA breaks) with alkaline filter elution. The compounds tested included various categories of chemicals (i.e., pesticides, industrial chemicals, cytostatics, and mycotoxins) most of which are directly acting genotoxicants (i.e., reacting with DNA either spontaneously or via metabolic activation). In addition, a few indirect genotoxic and nongenotoxic reproductive toxicants were included. Six of the chemicals induced no significant levels of ssDNA breaks in human and rat testicular cells: methoxychlor (10 to 100 ÁM, human and rat), benomyl (10 to 100 ÁM, human and rat), thiotepa (10 to 1000 ÁM, human and rat), cisplatin (30 to 1000 ÁM, human; 100 to 1000 ÁM, rat), Cd2+ (30 to 1000 ÁM, human; 100 to 1000 ÁM, rat), and acrylonitrile (30 to 1000 ÁM, human; 30 to 300 ÁM, rat). Four chemicals induced significant levels of ssDNA breaks in testicular cells from both species: styrene oxide (>/= 100 ÁM, rat and human), 1,2-dibromoethane (EDB) (>/= 100 ÁM, rat; 1000 ÁM human), thiram (>/= 30 ÁM, rat; >/= 100 ÁM, human), and chlordecone (300 ÁM, rat; >/=300 ÁM, human). Finally, five chemicals induced ssDNA breaks in one of the two species. Four chemicals induced significant ssDNA breaks in rat testicular cells only: 1,2-dibromo-3-chloropropane (DBCP) (>/= 10 ÁM), 1,3-dinitrobenzene (1,3-DNB) (>/= 300 ÁM), Cr6+ (1000 ÁM, and aflatoxin B1 (>/= 100 ÁM), the last two of these produced only a minor positive response. One chemical, acrylamide, induced a marginal increase in ssDNA breaks in human at 1000 ÁM but not in rat testicular cells. Although based on a limited number of donors, the data indicate a close correlation between the induction of DNA damage in human and rat testicular cells in vitro. For some chemicals, however, there appears to be differences in the susceptibility to chemically induced ssDNA breaks of isolated testicular cells from the two species. The data indicate that the parallel use of human and rat testicular cells provides a valuable tool in the assessment of human testicular toxicity.

Abstract  #Recently, we inserted the plasmid vector pKK233-2 containing rat GSH S-transferase (GST) 5-5 cDNA into Salmonella typhimurium TA1535 and found that these bacteria (GST 5-5(+)) expressed the protein and produced mutations when ethylene or methylene dihalides were added (Thier, R., Taylor, J. B., Pemble, S. E., Ketterer, B., Persmark, M., Humphreys, W. G., and Guengerich, F. P. (1993) Proc. Natl. Acad. Sci. U.S.A. 90, 8576-8580). After exposure to the known GST 5-5 substrate 1,2-epoxy-3-(4'-nitrophenoxy)propane, the GST 5-5(+) strain showed fewer mutants than the bacteria transfected with the cDNA clone in a reverse orientation (GST 5-5(-)), suggesting a protective role of GST 5-5. However, mutations were considerably enhanced in the GST 5-5(+) strain (as compared to GST 5-5(-)) when 1,2,3,4-diepoxybutane (butadiene diepoxide) or 1,2-epoxy-4-bromobutane was added. The GST 5-5(+) and GST 5-5(-) bacterial stains showed similar responses to 1,2-epoxypropane, 3,4-epoxy-1butene, and 1,4-dibromobutane. The results suggest that some bifunctional activated butanes are transformed to mutagenic products through GSH conjugation. We also found that the GST 5-5(+) strain showed enhanced mutagenicity with 1,4-dibromo-2,3-epoxybutane, 1,2-epoxy-3-bromopropane (epibromohydrin), and (+-)-1,4-dibromo-2,3-dihydroxybutane. The possibility was considered that a 5-membered thialonium ion may be involved in the mutagenicity. Model thialonium compounds were rather stable to hydrolysis in aqueous solution at pH 7.4 and slowly alkylated 4-(4-nitrobenzyl)pyridine. The presence of ahydroxyl group beta to the sulfur did not enhance reactivity. Mechanisms involving episulfonium ions are considered more likely. Potential oxidation productsof the toxic pesticide 1,2-dibromo-3-chloropropane (DBCP) were also consideredin this system. DBCP itself gave rather similar results in the two strains. Others have reported that oxidation of DBCP is required for mutagenicity, along with GSTcatalyzed GSH conjugation (Simula, T. P., Glancey, M. J., Soderlund, E. J., Dybing, E., and Wolf, C. R. (1993) Carcinogenesis 14, 2303-2307). The putative oxidation product 1,2-dibromopropional did not show a difference between the two strains. However, 1,3-dichloroacetone, a model for the putative oxidation product 1-bromo-3-chloroacetone, was considerably more mutagenic in the GST 5-5(+) strain.

Abstract  The agriculturally important nematocide 1,2-dibromo-3-chloropropane (DBCP) has been implicated as a cause of human male sterility. A survey at the Michigan Division of The Dow Chemical Company included measurements of semen samples, testicular size, and serum follicle-stimulating hormone (FSH), luteinizing hormone (LH), and testosterone in 232 chemical workers with past potential exposures to DBCP and in 97 nonexposed comparison employees. Potentially exposed groups showed significantly higher, although not abnormal, mean levels of FSH and LH. In the subgroup with the highest potential exposure ending subsequent to 1972, greater duration of exposure correlated with lower sperm count, higher FSH level, and smaller testicular volume. Mean values for this latter time-divided subgroup were not abnormal. The findings are consistent with a testicular effect of DBCP and also with reversibility of that effect over time.

Abstract  Dibromochloropropane (DBCP) was administered orally to 36 sexually mature male Dutch Belted rabbits assigned at random to one of six groups to receive 0, 0.94, 1.88, 3.75, 7.5, or 15.0 mg DBCP per kilogram of body weight daily 5 days per week during a 69-day treatment period. Animals were euthanized and necropsied on Day 70. Body weights and weights of the kidneys, liver, epididymides, and accessory sex glands were not influenced by DBCP treatment. The highest dosage reduced mean paired testes weight to 45% of control values (p less than 0.01). Mean seminiferous tubular diameter was reduced by 15 and 29% with the two highest dosages of DBCP, respectively (p less than 0.01), and the percentage of seminiferous tubules containing elongating and round spermatids, as the most advanced cell type present, was decreased (p less than 0.01). The number of leptotene primary spermatocytes per Sertoli cell, and the numbers of spermatogonia, young and old primary spermatocytes, and Step 1 spermatids per Stage I seminiferous tubular cross section likewise indicated a general depression (p less than 0.01) of spermatogenesis. Based upon the number of Step 1 spermatids per cross section at Day 70, production of sperm at this time by rabbits receiving the highest dose of DBCP was estimated to be less than one-fourth of control values. No significant effect (p greater than 0.05) of 0.94 mg DBCP/kg on any parameters was found, so this could be considered to be the no effect dose. However, the regressions and mean values are interpreted to indicate that the no effect level of DBCP may be less than 0.94 mg DBCP/kg of body weight. It is suggested that the most sensitive tests described here be included in future screening tests for potential effects of agents on male reproduction.

Abstract  Male pesticide applicators who worked with the nematocide dibromochloropropane (DBCP) were examined to determine the possible testicular toxicity from this exposure. Infertility and azoospermia which were first noted among factory workers exposed to DBCP were not observed among the applicators. Sperm count depression, however, was associated with the duration of exposure in the current year but not with exposure in past years. The extent of exposure to DBCP in the current year was also associated with an elevation of serum follicle stimulating hormone (FSH) but not of luteinizing hormone (LH). Sperm count depression was limited to applicators involved in irrigation setup work and in the calibration of equipment. These results suggest that the testicular toxicity of DBCP for men may occur in a shorter period than was previously reported, that the effect may be reversible in men with mild sperm count depression, and that public health measures might be directed at controlling specific application techniques.

Abstract  The soil fumigant 1,2-dibromo-3-chloropropane (I) undergoes hydrolysis in the rat to a series of epoxide metabolites. Alkylation of glutathione by these epoxides produces 2 urinary metabolites identified as the mercapturic acids VI (R=COCH3) and VII (R-COCH3). Hydrolysis of the epoxides produces the male antifertility agents alpha-chlorohydrin (IX, X-Cl) and alpha-bromohydrin (IX, X-Br) which are oxidatively metabolized to oxalic acid (XII), thus causing renal damage. These metabolic pathways can explain the toxic nature of the fumigant as a carcinogen, a male chemosterilant and as an agent causing kidney damage.

Abstract  A method has been developed for monitoring industrial workers and others exposed to environmental agents which may impair fertility. National birth probabilities specific for maternal birth cohort, age, parity, and race are used to derive expected fertility. Observed fertility is obtained by questionnaire. Standardized fertility ratios are computed for exposure and non-exposure periods and compared. The analytic techniques have been validated by applying the method to a group of 36 male factory employees working in an agricultural chemical division (ACD) where pesticides including the nematocide dibromochloropropane were formulated. Twelve of these employees in mid-1977 had been discovered to have severely depressed sperm counts related to occupational exposure. The standardized fertility ratio (SFR) computed from data available in mid-1977 for the period at risk from employment in the ACD (SFR = 0.75) was significantly lower than those derived for the entire not-at-risk period (SFR = 1.88) and the portion related to employment in other areas of the factory (SFR = 2.16). Similar differences also were evident from data available several years earlier, demonstrating that the surveillance technique would have been capable of detecting occupationally induced infertility among these workers in advance of the actual discovery date.

Abstract  This study represents the largest series to date documenting the gonadotoxic effect in humans of dibromochloropropane, a widely used pesticide. Three semen analyses, serum hormonal determinations (luteinizing hormone, follicle-stimulating hormone and testosterone) as well as genital examinations were completed for 228 workers at 2 chemical production sites and consisting of a dibromochloropropane-exposed and non-exposed cohort. Parameteric and non-parametric statistical analyses of the data sets of the sperm densities from the 2 subpopulations demonstrated statistical significance (p less than 0.10) at the short-term (1.5 years) manufacturing plant. Log transformation of the sperm count and hourly exposure data were necessary to develop meaningful statistical conclusions. The serum concentration of follicle-stimulating hormone as a group mean was significantly greater at both production sites for the exposed cohort when compared to the non-exposed participants but decreased by 10 levels of magnitude when the group demonstraing shorter but more recent exposure was compared to those from the plant with longer chemical production. Finally, a dose-response model suggested significant changes in sperm density at the short-term but more recently operated production site when more than 100 adjusted hours of exposure were exceeded, while the longer operated but longer closed facility demonstrated a significant impairment only when more than 1,000 adjusted hours of dibromochloropropane exposure were surpassed. This difference in exposure data may reflect regenerative changes in the tests once the gonadotoxic substance had been removed but exact nature of the dibromochloropropane effect and the possibility of a "no effect" concentration remain to be defined clearly.

Abstract  Although the mutagenic effect of Dibromochloropropane (DBCP) on experimental mammal systems has been described, its possible effect on the human genome has not yet been investigated. The present study describes the results of chromosomal analysis and health evaluation of offspring conceived to families during and after paternal exposure to DBCP. Ten children conceived during or following severe exposure and four who were conceived prior to DBCP exposure were evaluated. The chromosomal constitution of peripheral lymphocytes was normal in all cases. The mode of delivery, birth weight, physical examination and growth pattern were normal. No congenital malformations were detected. One spontaneous abortion out of 23 pregnancies was recorded. These results suggest that paternal exposure to DBCP, severe enough to cause azoospermia or oligozoospermia did not alter the paternal sperm genome or the chromosomal constitution of offspring conceived during or after exposure. This is further supported by the excellent health and lack of malformations among the children, along with the low rate of spontaneous abortions in the families studied.

Abstract  Groups of 10 male New Zealand white rabbits were exposed by inhalation to 0, 0.1, 1.0 or 10 ppm of 1,2-dibromo-3-chloropropane (DBCP) vapor for 6 hours/day, 5 days/week for 14 weeks, except that the 10 ppm group was exposed for only 8 weeks due to mortality. The semen of rabbits was evaluated on a weekly basis during the exposure period and at periodic intervals during a recovery period (32 weeks for all groups except the 10 ppm groups which was for 38 weeks). In order to assess the fertility of the exposed rabbits, each male was allowed to mate with an unexposed female at the 14th and 41st week of the study. Exposure of rabbits to 1 and 10 ppm of DBCP by inhalation produced adverse reproductive effects as well as decreases in sperm count, motility and viability. Rabbits treated at 1 and 10 ppm had decreased sperm counts between the 8th and 14th weeks of the study. All of the 10 ppm rabbits were infertile when mated during the 14th week. The effects of DBCP on spermatogenesis were shown to be essentially reversible in rabbits exposed to 1 ppm; however, at 10 ppm, recovery was not complete under the conditions of the test. Rabbits exposed to 10 ppm had severe testicular alterations as early as 4 weeks into the study and these progressed to severe testicular atrophy by 8 weeks. Those exposed to 1 ppm for 14 weeks developed moderate testicular atrophy (approximately 50% reduction in size). Following the recovery period, the rabbits in the 10 ppm group had evidence of partial reversibility of the testicular atrophy. Electron microscopic evaluation of testicular tissue confirmed findings by light microscopy effects and also indicated increased numbers of abnormal sperm within the seminiferous tubules of rabbits at both the 10 and 1 ppm exposure levels. Those exposed to 0.1 ppm had an equivocal increase in abnormal sperm after the 14-week exposure period but not after the recovery period. Based on these results 0.1 ppm level of DBCP is considered as a no effect level for reproductive parameters.

Abstract  The nematocide DBCP (1,2-dibromo-3-chloropropane) produced negative results in a specific-locus test for gene-mutation induction in the germline of male (101 X C3H)F1 mice, most of which were treated with 5 daily intraperitoneal injections of 80 mg/kg (total exposure, 400 mg/kg); a few received lower exposures. For treated spermatogonial stem cells, the finding of 2 mutations among 39519 offspring--a rate almost identical to the control rate--rules out (at the 5% significance level) an induced mutation frequency greater than 2.0 times the historical control rate. From treated poststem-cell stages, no mutants were found among 6240 offspring, ruling out (at the 5% significance level) a multiple of 8.0 times the control for these cell types. A multiple rearrangement (7 chromosomes involved in 3 translocations) found in one of the mutants probably arose as a postmeiotic event not associated with the DBCP treatment. The fertility of DBCP-treated males was not disturbed, in keeping with the absence of germ-cell toxicity and dominant lethals found by other investigators in these mice, and in contrast to results in certain other species. While the treated (101 X C3H)F1 mice are Ah-responsive, other findings make it questionable whether biotransformation of DBCP to reactive intermediates is accomplished via the Ah-receptor system.

Abstract  The use of indirect standardization in the assessment of the fertility of occupationally exposed workers is briefly reviewed and critiqued. The calculation of expected births in the method of Levine et al. (J Occup Med 1980;22:781-91) is modified to eliminate negative bias. An example is given using data from a 1977 survey of 60 male workers at a chemical manufacturing plant in Denver, Colorado, who were exposed to dibromochloropropane. The example illustrates how in-plant nonexposed reproductive experience provides a valuable supplement to US fertility tables which are specific only to race, birth cohort, age, and parity. It is also shown, however, that explicit control for potential confounding factors not included in the tables, such as marital status and surgical sterilization, can actually create rather than alleviate confounding error. This occurs when the additional factors co-vary in the reference population with the factors already included in the tables. For martial status, the control-induced error was readily minimized by restricting analysis to married experience at parity one or greater. For surgical sterilization, the corresponding error could not be reduced without severely compromising sample size, and hence control of this potential confounder in similar circumstances is not recommended.