Uncertainty factor toxicants

Toxicologists tend to focus their attention primarily on c.xtrapolations from cancer bioassays. However, tlicrc is also a need to evaluate the risks of lower doses to see how they affect the various organs and systems in the body. Many scientific papers focused on tlic use of a safety factor or uncertainty factor approach, since all adverse effects other than cancer and mutation-based dcvclopmcnUil effects are believed to have a tlu cshold i.e., a dose below which no adverse effect should occur. Several researchers have discussed various approaches to setting acceptable daily intakes or exposure limits for developmental and reproductive toxicants. It is Uiought Uiat an acceptable limit of exposure could be determined using cancer models, but today tliey arc considered inappropriate because of tlircsholds. ... 

The NOAEL is selected based in part on the assumption that, if the critical toxic effect is prevented, then all toxic effects are prevented. The NOAEL for the critical toxic effect should not be confused with the "no-obscrx cd-cffcct-lcvel" (NOEL). In some studies, only LOAEL rather than a NOAEL is available. The use of a LOAEL. however, requires the use of an additional uncertainty factor (as seen below). 

The RfD is derived from the NOAEL (or LOAEL) for the critical toxic effect by consistent application of uncertainty factors (UFs) and a modifying factor (ME). The uncertainty factors generally consist of multiples of 10 (although values less than 10 are sometimes used), with each factor representing a specific area of uncertainty inherent in the extrapolation from the available data. The bases for application of different uncertainty factors are explained below. 

Monomethyltirf. Acute toxicity studies were identified for monomethyltin for algae, invertebrates, and fish. Chronic NOECs were available for algae and invertebrates. A chronic NOEC of 0.007 mg/1 for monomethyltin chloride in Scenedesmus subspica-tus was the lowest reported result. Since there were no long-term test results available for fish, it was necessary to apply an uncertainty factor of 50 to the critical study. 

Monobutyltirr. Four acute toxicity studies were identified for monobutyltin chloride. The critical study was an acute EC50, based on immobilization, for Daphnia magna at a concentration of 25 mg/1. All four tests were acute, and, in the absence of long-term tests, it was decided to apply an uncertainty factor of 1000. 

PEL Pg pmol PHS PMR ppb ppm ppt REL RfD RTECS sec SCE SIC SIR SMR STEL STORET TLV TSCA TRI TRS TWA u.s. UF yr WHO wk permissible exposure limit picogram picomole Public Health Service proportionate mortality ratio parts per billion parts per million parts per trillion recommended exposure limit Reference Dose Registry of Toxic Effects of Chemical Substances second sister chromatid exchange Standard Industrial Classification Standardized incidence ratio standard mortality ratio short term exposure limit STORAGE and RETRIEVAL threshold limit value Toxic Substances Control Act Toxics Release Inventory total reduced sulfur time-weighted average United States uncertainty factor year World Health Organization week... 

For most chemicals, actual human toxicity data are not available or critical information on exposure is lacking, so toxicity data from studies conducted in laboratory animals are extrapolated to estimate the potential toxicity in humans. Such extrapolation requires experienced scientific judgment. The toxicity data from animal species most representative of humans in terms of pharmacodynamic and pharmacokinetic properties are used for determining AEGLs. If data are not available on the species that best represents humans, the data from the most sensitive animal species are used to set AEGLs. Uncertainty factors are commonly used when animal data are used to estimate minimal risk levels for humans. The magnitude of uncertainty factors depends on the quality of the animal data used to determine the no-observed-adverse-effect level (NOAEL) and the mode of action of the substance in question. When available, pharmocokinetic data on tissue doses are considered for interspecies extrapolation. 

Several studies with rats support the AEGL-3 values. A 10-min exposure to aniline at 15,302 ppm resulted in no toxic effects, and a 4-h exposure at 359 ppm resulted in severe toxic effects but no deaths. Dividing these values by a total uncertainty factor of 100 and scaling across time using C%t=k results in values similar to those derived from the Kim and Carlson (1986) study. Studies with repeated exposures of rats resulted in additional effects on the blood and spleen, but concentrations up to 87 ppm, 6 h/d, 5 d/w for 2 w were not disabling or life-threatening. 

Data Adequacy The key study was well designed, conducted, and documented. Values were presented graphically. Supporting data were sparse, probably because aniline is not a vapor at room temperature, and poisonings have involved contact with the liquid. Although human data are sparse, it is believed that a total uncertainty factor of 100 is protective of human health. Because aniline is absorbed through the skin, which increases the systemic toxicity, direct skin contact with the liquid would be additive and result in onset of adverse effects at airborne concentrations below the respective AEGL values. Therefore, direct skin contact with the liquid should be avoided. 

Uncertainty Factors/Rationale Total uncertainty factor 30 Interspecies 10—The 10-min LC50 value for the monkey was about 60% of the rat value and one-third the rabbit value. The mouse data were used to calculate the AEGL levels, because the data exhibited a good exposure-response relationship and the endpoint of decreased hematocrit levels can be considered a sensitive indicator of arsine toxicity. In addition, arsine has an extremely steep dose-response relationship, allowing little margin in exposure between no effects and lethality. 

Intraspecies Because the species used was the most sensitive to monomethylhydrazine toxicity and the most closely related to humans, an uncertainty factor of 3 is justified. A factor of 3 was used. Although the mechanism of toxicity is uncertain and sensitivity among individuals may vary, the exposure-response relationship is steep, suggesting limited variability in the toxic response to methylhydrazine. Furthermore, it is likely that acute toxic responses are, at least initially, a function of the extreme reactivity of methylhydrazine. The interaction of the highly reactive monomethylhydrazine with tissues (e.g., pulmonary epithelium) is not likely to greatly vary among individuals. 

Uncertainty factors An uncertainty factor of 3 for interspecies variability was applied because the toxic response to dimethylhydrazine... 

Data adequacy The key study was well designed and conducted and documented a lack of effects on heart and lung parameters as well as clinical chemistry. Pharmacokinetic data were also collected. The compound was without adverse effects when tested as a component of metered-dose inhalers on patients with COPD. Animal studies covered acute, subchronic, and chronic exposure durations and addressed systemic toxicity as well as neurotoxicity, reproductive and developmental effects, cardiac sensitization, genotoxicity, and carcinogenicity. The values are supported by a study with rats in which no effects were observed during a 4-h exposure to 81,000 ppm. Adjustment of the 81,000 ppm concentration by an interspecies and intraspecies uncertainty factors of 3 each, for a total of 10, results in essentially the same value (8,100 ppm) as that from the human study. ... 

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