Dose-response relationships unusual

The criterion employed for a positive response in this assay is a reproducible statistically significant increase in mutation frequency (weighted mean for duplicate treated cultures) over the concurrent vehicle control value (weighted mean for four independent control cultures). Ideally, the response should show evidence of a dose-response relationship. When a small isolated significant increase in mutation frequency is observed in only one of the two duplicate experiments, then a third test should be carried out. If the third test shows no significant effects, the initial increase is likely to be a chance result. In cases where an apparent treatment-related increase is thought to be a result of unusually low variability or a low control frequency, comparison with the laboratory historical control frequency may be justified. 

Pharmacokinetics has played a crucial and somewhat unusual role in the assessment of health risks from methylmercury. Some of the epidemiology studies of this fish contaminant involved the measurement of mercury levels in the hair of pregnant women, and subsequent measurements of health outcomes in their offspring (Chapter 4). Various sets of pharmacokinetic data allowed estimation of the level of methylmercury intake through fish consumption (its only source) that gave rise to the measured levels in hair. In this way it was possible to identify the dose-response relationship in terms of intake, not hair level. Once the dose-response relationship was established in this way, the EPA was able to follow its usual procedure for establishing an RfD (which is 0.1 ag/(kg b.w. day)). 

List the toxic effects of vinyl chloride. One of these shows an unusual dose-response relationship. Briefly describe and explain this. Name any toxic metabolites produced by metabolism of this compound. 

Classification of chemically induced hepatotoxicity is primarily based upon pattern of incidence and histopathological morphology. Intrinsic hepatotoxic drugs demonstrate a broad incidence, dose-response relationship and will usually give similar results in humans and experimental animals. The incidence of liver damage from idiosyncratic hepatotoxicants is limited to susceptible individuals and results from hypersensitivity reactions or unusual metabolic conversions that can occur due to polymorphisms in drug metabolism genes (see Chapters 11 and 13). 

The answer is 4 f/ B 2L Idfosyncratic reactions are unexpected responses because they generally do not demonstrate an obvious dose-response relationship and often cannot be predicted by toxicologic testing. The unusual susceptibility is often due to lack of mechanisms for rnetabolism or detoxification. 

Some drugs exhibit unusual concentration/response relationships, which minimizes the utility of TDM. In these cases, clinical response correlates more with duration of dosing than the actual dose or resultant plasma concentrations. 

The fact is scientists do not know the dose—response relation at very low risks for any carcinogen. The various hypothesized relationships have different degrees of scientific support but none has been documented with anything like the degree of rigor usually sought by scientists. Moreover, different low dose extrapolation models can yield markedly different estimates of risk, with variations of 100- or 1000-fold not unusual. Here s another issue left to the unhappy risk assessor to resolve. 

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