Metabolite hazards

Since endosulfan is a cytochrome P450-dependent monooxygenase inducer, the quantification of specific enzyme activities (e.g., aminopyrine-A -demethylase, aniline hydroxylase) may indicate that exposure to endosulfan has occurred (Agarwal et al. 1978). Because numerous chemicals and drugs found at hazardous waste sites and elsewhere also induce hepatic enzymes, these measurements are nonspecific and are not necessarily an indicator solely of endosulfan exposure. However, these enzyme levels can be useful indicators of exposure, together with the detection of endosulfan isomers or the sulfate metabolite in the tissues or excreta. 

An environmental protocol has been developed to assess the significance of newly discovered hazardous substances that might enter soil, water, and the food chain. Using established laboratory procedures and C-labeled 2,3,7,8-tetra-chlorodibenzo-p-dioxin (TCDD), gas chromatography, and mass spectrometry, we determined mobility of TCDD by soil TLC in five soils, rate and amount of plant uptake in oats and soybeans, photodecomposition rate and nature of the products, persistence in two soils at 1,10, and 100 ppm, and metabolism rate in soils. We found that TCDD is immobile in soils, not readily taken up by plants, subject to photodecomposition, persistent in soils, and slowly degraded in soils to polar metabolites. Subsequent studies revealed that the environmental contamination by TCDD is extremely small and not detectable in biological samples. 

Stages in hazard characterization according to the European Commission s Scientific Steering Committee are (1) establishment of the dose-response relationship for each critical effect (2) identification of the most sensitive species and strain (3) characterization of the mode of action and mechanisms of critical effects (including the possible roles of active metabolites) (4) high to low dose (exposure) extrapolation and interspecies extrapolation and (5) evaluation of factors that can influence severity and duration of adverse health effects. 

Benchmark 4 Prefer - Safer Chemical. Only organic chemicals with low inherent toxicity to humans and wildlife, that do not bio accumulate, and rapidly and completely degrade to benign degradation products or metabolites reach Benchmark 4. These are chemicals that would meet the principles of green chemistry that relate to hazard. 

The Green Screen includes a chemical s breakdown products, that is, metabolites and degradation products in a hazard assessment because they may be more hazardous than the parent compound. The final benchmark for a parent chemical is the lowest benchmark achieved by either it or its breakdown products. For example, if a parent chemical achieved Benchmark 2, but its breakdown product achieved Benchmark 1, the final benchmark for the parent chemical is Benchmark 1. Thus the degradation product or metabolite of a chemical is considered equivalent to the parent compound with respect to its benchmark unless it can be demonstrated that the breakdown product is insignificant (i.e., transient, not actually formed, etc.). 

The Ames test involves the reversion from a his— to his+ phenotype in any one of multiple bacterial strains (usually five strains are tested simultaneously). If the addition of test compound to a his— strain of bacteria allows them to grow on histidine deficient media, the obvious conclusion is compound-induced mutagenesis and a high potential hazard for the compound being carcinogenic. This test can also be conducted in the presence or absence of metabolic activation, in order to provide more information on potential risks (i.e., the parent compound may not be mutagenic, but the primary metabolite may present a safety risk). In practice, a positive Ames test almost always leads to discontinuing work on a compound of interest, and so these data are always collected prior to nomination of a compound for development. 

DDT was historically used in Spain as a pesticide from the mid-1950s to mid-1960s [51] but, as it forms hazardous metabolites as it breaks down, its use was restricted... 

Interaction effects of mercury with other contaminants, such as herbicides and pesticides, could intensify hazards to avian populations (Mullins et al. 1977). For example, a striking parallel exists between levels of Hg and of DDT and its metabolites in birds of prey, suggesting the existence of common ecotoxicological mechanisms (Delbeke et al. 1984 Wiemeyer et al. 1984) additional research is clearly needed. 

The lethal effect of technical chlordane in birds is attributed primarily to chlordane metabolites, especially oxychlordane and, to a lesser extent, heptachlor epoxide (Shekel et al. 1983). Oxychlor-dane was the most persistent chlordane component in avian brain tissues. The half-time persistence of oxychlordane in brain was 63 days, and 95% loss was estimated in 280 days. The Tb 1/2 for heptachlor epoxide was 29 days, and for /ran.v-nonachlor it was 19 days (Shekel et al. 1979). Oxychlordane residues in brain tissue approaching 5 mg/kg FW were considered within the lethal hazard zone to birds (Shekel et al. 1979). 

Exposure Levels in Humans. The database for -hexane exposure levels in humans is limited to a few older detections of -hexane in breast milk and determinations of levels in body fluids and alveolar air collected in foreign countries. A more current and complete database would be helpful in determining the current exposure levels, thereby permitting the estimation of the average daily dose associated with various scenarios (e.g., living near a hazardous waste site). Since -hexane is rapidly metabolized within the human body, further studies correlating levels in the environment with the levels of metabolites and biomarkers in humans would be helpful. This information is necessary for assessing the need to conduct health studies on these populations. 

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