Methyl Bromide Risk Characterization in California (2000) / Chapter Skim
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2 Toxicology and Hazard Identification
2 Toxicology and Hazard Identification
Pages 12-34
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From page 12... ...
In Table 2-l beTow, taken from the DPR risk characterization document (DPR 1999, p.
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a Adult Child RfC(ppb) b 21 na 210 Effect in Animal Studies Developmental toxicity (pregnant rabbit)
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Although the discussion on the absorption, distribution, and excretion of '4C-labeled methyl bromide (based on following the radiolabel) in the DPR reports appears complete, there is only limited discussion of its metabolism.
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~ 995~. In the case of sister chromatic exchanges in blood cells exposed in vitro to methyl bromide, cells from fast conjugators appeared to be protected from the production of sister chromatic exchanges, whereas cells from slow conjugators were not.
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A dose-related increase in the frequency of sister chromatic exchanges in bone marrow of female mice exposed to concentrations of methyl bromide at 100 or 200 ppm for 10 days was reported (NTP 1992~. However, this was not seen in another study in which mice were exposed to a concentration of methyl bromide at 120 ppm for 12 weeks (NTP 1992~.
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Because methyl bromide is a direct-acting mutagen, especially in in vitro systems, some discussion for its lack of correlation with carcinogenicity should be presented in the DPR report. ACUTE TOXICITY In Section ITT.B of the DPR report, four rat, one mouse, two dog and one guinea pig inhalation toxicity studies were examined for acute effects, as were one rat and one rabbit inhalation developmental studies, and one dog oral study.
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From page 18... ...
are not appropriate for regulatory purposes because these studies examined neurochemical endpoints that are not necessarily indicative of toxicity. In addition to neurotoxicity, DPR also considered developmental toxicity for its acute exposure risk assessment, based on the assumption that only a single exposure at a critical time is necessary for the induction of a developmental effect.
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Therefore, the subcommittee concurs with the selection of studies by DPR as the critical studies for subchronic toxicity. ClIRONIC INHALATION AND ONCOGENICITY Two chronic inhalation studies were reviewed by DPR for the assessment of the chronic toxicity and oncogenicity of methyl bromide (Section TTT.D)
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The second chronic inhalation study reviewed by DPR was conducted by the National Toxicology Program (NTP 1992~. This chronic study with BSC3F1 mice included neurobehavioral evaluations at 3-month intervals and
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This study was not considered acceptable by either DPR or the subcommittee because the study was reported in summary form and individual data were not available for evaluation. The t~vo-generation reproduction study by American Biogenics Corporation (1986)
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REPRODUCTIVE TOXICITY Two reproductive toxicity studies were evaluated in Section III.F of the DPR report. Both studies used rats as the experimental animals; one was an inhalation study (American Biogenics Corporation 1986; Hardisty 1992, as
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These should also be mentioned in Section ITT.G under developmental effects. The significant, dose-dependent reductions in the body weights during lactation of the offspring of all four mating trials might be due to gestational or lactational exposure to methyl bromide.
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These data are consistent with the results of the inhalation study discussed above (American Biogenics Corporation 1986; Hardisty 1992, as cited in DPR 1999; Busey 1993, as cited in DPR 1999) that found no effects on fertility indices of the F0 generation exposed for up to 105 days before mating.
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studies suggest that methyl bromide might affect the development of the reproductive system, but the subcommittee does not agree that the studies support DPR's conclusion that methyl bromide is a direct reproductive toxicant in adult animals. DEVELOPMENTAL TOXICITY Four inhalation and two oral exposure studies in two species were reviewed by DPR for the assessment of the developmental toxicity of methyl bromide (Section TIT.G)
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Nonetheless, it provides evidence that gestational exposure to 20 ppm methyl bromide from gestation days ~ to 15 does not cause developmental toxicity in rabbits. TABLE 2-3 Summary of Skull Ossification Defects in Sikov et al.
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However, fetal and gravid uterine weights were also significantly decreased in Part 2 and gravid uterine weights were nonsignificantly reduced in the 40- and 80-ppm groups compared with controls in Part I, suggesting that the reduced maternal weight gain might represent a developmental effect rather than or in addition to a maternal effect. In Section T.C of the DPR report (1999, p.
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(1998) studied the developmental toxicity of oral methyl bromide exposure in rats (at 0, 3, 10, or 30 mg/kg/day, gestation days 6 to 15)
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1981~. In rabbits, the evidence for developmental toxicity includes gallbladder agenesis, reduced fetal weights, and increased frequency of fused sternebrae (Breslin et al.
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1986~; these human observations suggest toxic endpoints that need to be considered for a health-protective risk characterization. SELECTION OF CRITICAL EFFECTS FOR ACUTE TOXICITY The use of a developmental toxicity study for the assessment of the risks of acute exposure to methyl bromide is a reasonable one, given the principle that a single gestational exposure is sufficient to produce an adverse developmental effect, and in light of the large numbers of women of childbearing age in the workforce.
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One, alluded to above, is that the findings of this study, taken on their own, might be considered equivocal evidence for developmental toxicity. The three significant effects fetal weight decline, fused sternebrae, and gallbladder agenesis were not statistically consistent between Parts 1 and 2 of the stu(ly.
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(199Ob) developmental toxicity study to determine the critical NOAEL for acute toxicity for workers and residents appears to be a conservative approach, but one that is justified in the absence of additional data that show that a single exposure at the time of galIbladder development does not cause galIbladder agenesis.
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