hexachlorobutadiene - Davidborowski.com
hexachlorobutadiene - Davidborowski.com hexachlorobutadiene - Davidborowski.com
HEXACHLOROBUTADIENE 44 2. HEALTH EFFECTS action of γ glutamyl transferase which removes the glutamate from the glutathione tripeptide followed by the action of a peptidase that removes the glycine from the carboxy terminus. The cysteine derivative is further metabolized to simpler sulphur derivatives through the action of β- lyase. β-Lyase is present in the rodent liver, intestines, and kidneys (MacFarlane et al. 1989; Jones et al. 1988). In the kidney, the highest concentration of β-lyase is located in the pars recta of the proximal tubule, the same area that is damaged by hexachlorobutadiene. It should be noted that β-lyase has been detected in the entire proximal segment (Jones et al. 1988). It is present in both the cytosol and mitochondria and is pyridoxal phosphate dependent (MacFarlane et al. 1989). It degrades the cysteine conjugate to pyruvate, ammonia, and one or more reactive thiols (Dekant et al. 1990b; Schnellmann et al. 1987). A highly reactive thioketene (Figure 2-3) may form as an intermediate and cause local tissue damage (Dekant et al. 1991; Koob and Dekant 1992). The effects of the cysteine conjugate on the activity of the cells of the proximal tubules was evaluated in cells from New Zealand white rabbits (Schnellmann et al. 1987). These studies indicate that the metabolites of the cysteine conjugate alter the action of the mitochondria in a two phase process. The first phase apparently causes an uncoupling of oxidative phosphorylation thereby preventing the generation of ATP. The deficiency of ATP in turn limits ATP dependent active transport in the tubules, inhibiting reabsorption processes. In the second phase, inhibition of cytochrome c-cytochrome oxidase activity and electron transport occur (Schnellmann et al. 1987). These changes result in cell damage as reflected in a decrease in the cellular retention of lactate dehydrogenase approximately 1 hour after exposure. The carcinogenic properties of hexachlorobutadiene are proposed to result from binding of the sulfenic acid degradation product or a thioketene intermediate to cellular DNA (Dekant et al. 1990b; Henschler and Dekant 1990). Cell necrosis is thought to stimulate replication of cells with altered DNA, enhancing tumorigenesis. 2.4 RELEVANCE TO PUBLIC HEALTH Data regarding the effects of exposure to hexachlorobutadiene on humans are sparse. Serum bile acids were increased in workers exposed to vapor concentrations of 0.005-0.02 ppm. These effects could not be attributed to hexachlorobutadiene alone because the workers were also potentially
HEXACHLOROBUTADIENE 45 2. HEALTH EFFECTS exposed to other chemicals (carbon tetrachloride and perchloroethylene) and there were no background data on employee health, smoking habits, alcohol consumption, or other confounding variables. Animals have been studied more extensively. Although there are studies available on the systemic (respiratory) effects following inhalation, data are not sufficient to identify a reliable NOAEL value by this route. Much of the available data involve oral exposures in rats. The primary health effect associated with intermediate-duration and chronic-duration oral exposures to hexachlorobutadiene is kidney damage, which occurred in this organ at doses of 0.2 to 20 mg/kg/day. The liver was affected to a lesser extent and effects occurred at doses of 6.3 or 15.6 mg/kg/day. Acute dermal studies, although limited, confirm the toxic effects of hexachlorobutadiene on these organs. Hexachlorobutadiene did not adversely affect reproduction in animals except at high doses (150 mg/kg/day for 10 weeks). Although there was some evidence of fetotoxicity in animals after inhalation (10 ppm) or oral (15 mg/kg/day) exposure, embryolethality and teratogenicity were not detected. Oral studies in animals indicate that hexachlorobutadiene may increase the risk of renal cancer at dose levels of 20 mg/kg/day. The effects of hexachlorobutadiene are most pronounced after repeated chronic exposure to low doses, suggesting that effects are cumulative. For this reason, there is greater concern for populations living near hazardous waste sites, where exposure to low levels may occur for long periods of time, than for acute exposure scenarios. Minimal Risk Levels for Hexachlorobutadiene Inhalation MRLs Inhalation MRLs have not been derived for any duration category due to the lack of sufficient data to identify a target organ and reliable NOAEL values. Oral MRLs • An MRL of 0.0002 mg/kg/day has been derived for intermediate-duration oral exposure to hexachlorobutadiene.
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HEXACHLOROBUTADIENE 45<br />
2. HEALTH EFFECTS<br />
exposed to other chemicals (carbon tetrachloride and perchloroethylene) and there were no<br />
background data on employee health, smoking habits, alcohol consumption, or other confounding<br />
variables. Animals have been studied more extensively. Although there are studies available on the<br />
systemic (respiratory) effects following inhalation, data are not sufficient to identify a reliable<br />
NOAEL value by this route. Much of the available data involve oral exposures in rats. The primary<br />
health effect associated with intermediate-duration and chronic-duration oral exposures to<br />
<strong>hexachlorobutadiene</strong> is kidney damage, which occurred in this organ at doses of 0.2 to 20 mg/kg/day.<br />
The liver was affected to a lesser extent and effects occurred at doses of 6.3 or 15.6 mg/kg/day.<br />
Acute dermal studies, although limited, confirm the toxic effects of <strong>hexachlorobutadiene</strong> on these<br />
organs.<br />
Hexachlorobutadiene did not adversely affect reproduction in animals except at high doses<br />
(150 mg/kg/day for 10 weeks). Although there was some evidence of fetotoxicity in animals after<br />
inhalation (10 ppm) or oral (15 mg/kg/day) exposure, embryolethality and teratogenicity were not<br />
detected. Oral studies in animals indicate that <strong>hexachlorobutadiene</strong> may increase the risk of renal<br />
cancer at dose levels of 20 mg/kg/day. The effects of <strong>hexachlorobutadiene</strong> are most pronounced after<br />
repeated chronic exposure to low doses, suggesting that effects are cumulative. For this reason, there<br />
is greater concern for populations living near hazardous waste sites, where exposure to low levels<br />
may occur for long periods of time, than for acute exposure scenarios.<br />
Minimal Risk Levels for Hexachlorobutadiene<br />
Inhalation MRLs<br />
Inhalation MRLs have not been derived for any duration category due to the lack of sufficient data to<br />
identify a target organ and reliable NOAEL values.<br />
Oral MRLs<br />
• An MRL of 0.0002 mg/kg/day has been derived for intermediate-duration oral exposure<br />
to <strong>hexachlorobutadiene</strong>.
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