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.

Abstract  The risk assessment process is an imprecise procedure aimed at determining a toxicant exposure level with an acceptable risk to the human population. The lack of precision is due to the uncertainties in the assumptions that must be made due to the lack of specific scientific information or knowledge of how to use certain types of data. Unfortunately, every necessary piece of information cannot be obtained for every chemical requiring a risk assessment. In order to better identify and understand some of the assumptions that are made in the risk assessment of reproductive and developmental toxicants, a workshop was organized to specifically define the assumptions underlying the risk assessments for seven specific toxicants (dibromochloropropane, dioxin, glycol ethers, heptachlor, lead, tetrahydrocannabinol, and vitamin A) and to determine the potential research which would reduce the uncertainty associated with making those assumptions. The major assumptions discussed centered around the topics of heterogeneous populations, thresholds, safety factors, exposure assessment, quantitative structure-activity relationships, and mechanisms. This report is the summary of the workshop discussions.

Abstract  The studies presented in this review indicate that perinatal exposure of the fetal or neonatal rodent to a toxicant can adversely affect reproductive development, reduce fertility and accelerate reproductive senescence. In rodents and humans exposure to DES, estrogens, androgens and progestins during critical developmental periods produce morphological and pathological alterations of the reproductive tract of males and females. DES treatment causes cancer, infertility and serious morphological abnormalities of the reproductive tract in all species examined.

Abstract  Biosis copyright: biol abs. rrm abstract ammonium nitrate ethylene dibromide simazine aldicarb atrazine dibromochloropropane 1 2 dichloropropane ground water contamination sister chromatid exchange micronucleus formation chromosome aberration

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  Procedures for conducting experimental studies of respiratory carcinogenesis are reviewed. Advantages and disadvantages of mice, rats, or hamsters in studies of respiratory carcinogenesis are assessed. Mice have the advantage of small size and short life span; hamsters are resistant to pulmonary infection, have a low spontaneous lung tumor incidence, and develop tumors similar to those of humans; and rats are sensitive to induction of nasal cancer by organic chemicals. Oncogenic responses from inhalation of organic chemicals are tabulated. Chemicals studied include: acetaldehyde (75070), acrylonitrile (107131), acrolein (107028), benzo(a)pyrene (50328), benzene (71432), bis(chloromethyl)ether (542881), chloromethylmethylether (107302), diazomethane (334883), 1,2-dibromo-3-chloropropane (96128), dichloroethylene (25323302), dimethylcarbamoylchloride (79447), epichlorohydrin (106898), ethylene-dibromide (106934), furfural (98011), ethylene-oxide (75218), formaldehyde (50000), hexamethyl-phosphoramide (680319), methylcholanthrene (56495), urethane (51796), polyurethane (9009545), tetrachloroethylene (127184), trichloroethylene (79016), vinyl-bromide (593602), and vinyl-chloride (75014). Oncogenic responses from inhalation of metallic and nonmetallic compounds are presented. Induction of respiratory tract tumors by cigarette smoke inhalation, ambient air and smog, engine emissions, fossil fuel derived smoke and fumes, dusts and solid aerosols, and liquid aerosols is discussed. The author concludes that despite the limitations in the use of animal inhalation experiments to predict the likelihood of cancer induction in humans, there are no clear cut better alternatives at present. Long term inhalation studies are likely to continue with the aid of new strains that more closely resemble human tumor types, pharmacokinetic factors, and metabolic processes.

Abstract  BIOSIS COPYRIGHT: BIOL ABS. RRM HUMAN CARCINOGENESIS HAZARDOUS SUBSTANCES EPA FDA OSHA

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  Large numbers and large quantities of endocrine-disrupting chemicals have been released into the environment since World War II. Many of these chemicals can disturb development of the endocrine system and of the organs that respond to endocrine signals in organisms indirectly exposed during prenatal and/or early postnatal life; effects of exposure during development are permanent and irreversible. The risk to the developing organism can also stem from direct exposure of the offspring after birth or hatching. In addition, transgenerational exposure can result from the exposure of the mother to a chemical at any time throughout her life before producing offspring due to persistence of endocrine-disrupting chemicals in body fat, which is mobilized during egg laying or pregnancy and lactation. Mechanisms underlying the disruption of the development of vital systems, such as the endocrine, reproductive, and immune systems, are discussed with reference to wildlife, laboratory animals, and humans.

Abstract  BIOSIS COPYRIGHT: BIOL ABS. RRM REVIEW HUMAN MONOOXYGENASE

Abstract  The levels and distribution of 55 volatile organic compounds (VOCs) were determined by purge and trap GC-MS on water samples from 30 sites within the urban rivers and estuaries of Osaka, a populated industrialized city of Japan. Forty of 55 target VOCs listed in the US EPA Method 524.2 were detected. Dichloromethane (DCM) was found at higher levels at all of the sampling sites. The distribution of dominant VOCs followed four different patterns. First, the most common VOCs (DCM, toluene, trichloroethene and tetrachloroethene) showed concentration maxima in the river segments, and the sites of maximum concentration fluctuated due to irregular large spills and/or loadings. Second, one VOC (cis-1,2-dichloroethene) was evenly distributed in particular rivers due to fixed loadings. Both of these patterns were found in the upper and middle reaches. Third, some of VOCs (1,2,3-trichloropropane and benzene) were specific to a single industrial site and truceable to those sources. Finally, some VOCs showed no concentration maxima along the rivers and entered from multiple sources (chloroform and bromadichloromethane). Diurnal variations of VOCs at the border of the city area, receiving domestic and industrial discharges, provided information to interpret their observed downstream distribution and possible sources. (C) 1997 Elsevier Science Ltd.

Abstract  Volatile organic compounds indicated in the US-EPA 502.2 method were detected in the drinking water of twenty-one public fountains of the City of Torino. The analyses were carried out with P&T, using as detectors the PID+HECD pair or an ion trap mass spectrometer. The concentration of organohalide species in each sample was below the limit permitted by law and the analytical results made it possible to identify at least two areas of the City with a different quality of water.

Abstract  Forty halogenated hydrocarbons of known rodent carcinogenicity (24 carcinogens, 16 noncarcinogens), including many promoters of carcinogenesis, nongenotoxic carcinogens, and hepatocarcinogens, were selected for study. The chemicals were administered by gavage in two dose levels to female Sprague-Dawley rats. The effects of these 40 chemicals on four biochemical assays [hepatic DNA damage by alkaline elution (DD), hepatic ornithine decarboxylase activity (ODC), serum alanine aminotransferase activity (ALT), and hepatic cytochrome P-450 content (P450)] were determined. Composite predictive parameters are defined as follows: CP = [ODC and P450], CT = [ALT and ODC], and TS = [DD or CP or CT]. The operational characteristics of TS for predicting rodent cancer were sensitivity 58%, specificity 81%, positive predictivity 82%, negative predictivity 57%, and concordance 68%. The concordance for the Ames test (45%) and structural alerts (SA; 46%) was much lower. TS also outperformed the Ames test and SA in producing fewer false positives (the specificity of TS was 81% vs. only 63% for the Ames test and 57% for SA). For predicting the carcinogenicity of the most difficult halogenated hydrocarbons (Ames and SA negative chemicals), TS was capable of successfully predicting the carcinogenicity of 8 (carbon tetrachloride, chloroform, alpha-hexachlorocyclohexane, kepone, mirex, monuron, p,p'-DDE, and 2,4,6-trichlorophenol) out of 16 of these non-DNA-reactive halogenated hydrocarbon carcinogens. All 8 of these halogenated hydrocarbons were positive in either CP or CT. This evidence shows that nongenotoxic carcinogenesis is best predicted by nongenotoxic parameters such as CP or CT (components of the predictor TS).

Abstract  A series of halogenated compounds was tested by oral intubation in 200 Osborne-Mendel rats and 200 B6C3F1 mice of both sexes. Carbon tetrachloride, used as a positive control, induced liver and adrenal tumors in mice and neoplastic nodules in the livers of rats. 1,2-Dibromoethane and 1,2-dibromo-3-chloropropane caused stomach tumors with many metastases in both rats and mice. Chloroform, known to cause hepatocellular carcinomas in mice, led in addition to kidney tumors in male rats. 1,2-Dichloroethane was much weaker than the analog, 1,2-dibromoethane, and induced only a few stomach tumors in rats. It increased liver and lung tumors in mice. Most of the compounds, namely, trichloroethylene, 1,1-dichloroethane, 1,1,2-trichloroethane, hexachloroethane, and tetrachloroethylene, increased hepatocellular carcinomas in mice but had little or no action in rats. Iodoform tended to increase thyroid tumors in male rats and hepatocellular carcinomas in male mice. The action of 3-chloropropene was questionable. No tumors could be attributed to 1,1,1-trichloroethane (methylchloroform).

Abstract  A comparison of target organs for mutagens and non-mutagens is presented for 351 rodent carcinogens in the Carcinogenic Potency Database (CPDB) with mutagenicity evaluations in Salmonella. Results are consistent with the hypotheses that in high-dose rodent tests mitogenesis is important in the carcinogenic response for mutagens and non-mutagens alike, and that mutagens have a multiplicative interaction for carcinogenicity because they can both damage DNA directly and cause cell division at high doses. These hypotheses would lead one to expect several results that are found in the analysis: First, a high proportion of both mutagens and non-mutagens induce tumors in rodent bioassays at the MTD. Second, mutagens compared to non-mutagens are: (a) more likely to be carcinogenic; (b) more likely to induce tumors at multiple target sites; and (c) more likely to be carcinogenic in two species. Among carcinogens that induce tumors at multiple sites in both rats and mice, 81% are mutagens; in comparison, among carcinogens that are positive at only a single target site in one species and are negative in the other, 42% are mutagens. Since tissue distribution and pharmacokinetics would not be expected to differ systematically between mutagens and non-mutagens, one would not expect systematic differences in the particular organs in which tumors are induced. Results do not support the idea that mutagens and non-mutagens induce tumors in different target organs. Both mutagens and non-mutagens induce tumors in a wide variety of sites, and most organs are target sites for both. Moreover, the same sites tend to be the most common sites for both: 79% or more of both mutagenic and non-mutagenic carcinogens are positive in each species in at least one of the 8 most frequent target sites: liver, lung, mammary gland, stomach, vascular system, kidney, hematopoietic system and urinary bladder. Species differences are discussed as well as results for particular target organs: liver, Zymbal's gland and kidney.

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.