Animal dosing

Toxicity. Many /V-nitrosamines are toxic to animals and cells in culture (4,6—8,88). /V-Nitrosodimethy1amine [62-75-9] (NDMA) is known to be acutely toxic to the Hver in humans, and exposure can result in death (89). Liver damage, diffuse bleeding, edema, and inflammation are toxic effects observed in humans as a result of acute and subacute exposure to NDMA. These effects closely resemble those observed in animals dosed with NDMA (89,90). 

Most immunotoxic responses express a clear dose-response relationship that can be used for human risk assessment. However, it is more difficult to extrapolate in vitro concentrations than in vivo animal doses (plasma concentrations) to the clinical dose. 

The soluble metabolites excreted from animals dosed by injection were collected on AmberliteR XAD-4 resin, the resin eluted sequentially with diethyl ether, acetone, and methanol, and the solutes separated by thin-layer chromatography on silica gel and quantitated by liquid scintillation counting. 

TABLE 5.3 Conversion of Animal Dose to Hnman Eqnivalent Dose (HED) Based on Body Snrface Area... 

Species To Convert Animal Dose in mg/kg to Dose in mg/m. Multiply by kg/m below To Convert Animal Dose in mg/kg to HED in mg/kg. Either Divide Animal Multiply Animal Dose by Dose by ... 

Used to derive acute inhalation Minimal Risk Level (MRL) of 0.05 ppm (50 ppb) animal dose extrapolated to human dose according to method of EPA (1989d) values of blood/air partition coefficients assumed to be equal for animals and humans dose adjusted for 1 ess-than-continuous exposure (8 hours/24 hours), and divided by an uncertainty factor of 100 (10 for extrapolation from animals to humans, and 10 for human variability). 

Gastrointestinal Effects. Although data are limited, the only systemic tissue that has been found to be affected following oral exposure is the epithelium of the stomach (Boorman et al. 1986 Danse et al. 1984). This is presumably a result of direct contact between bromomethane and the gastrointestinal epithelium. Based on this effect, an intermediate-duration oral MRL of 0.003 mg/kg/day has been derived. It is likely that this effect (which has only been observed in animals dosed with concentrated solutions of bromomethane dissolved in oil) would be much less pronounced if exposure occurred via ingestion of more dilute solutions of bromomethane in water. However, this has not been studied. 

The science policy components of risk assessment have led to what have come to be called default assumptions. A default is a specific, automatically applied choice, from among several that are available (in this case it might be, for example, a model for extrapolating animal dose-response data to humans), when such a choice is needed to complete some undertaking (e.g., a risk assessment). We turn in the next chapter to the conduct of risk assessment and the ways in which default assumptions are used under current regulatory guidelines. We might say we have arrived at the central subject of this book. 

Note When the dose for a given species is expressed in mg/kg body weight, the equivalent human dose (in mg/kg body weight) is obtained by dividing the animal dose by the scaling factor. 

Reference point on the animal dose-response curve... 

Animals dosed with " Ca extrinsically labeled beverages... 

Oral exposure of adult rats and mice caused effects on fertility in males and females and serious effects on the testicles. Young animals were much more sensitive to gonadal effects than adults and in some cases, the onset of occurrence of the testicular effects was earlier in young animals. Dose-dependent testicular effects were seen in young rats exposed to di(2-ethylhexyl) phthalate in the diet. 

Developmental Effects. Isophorone has been tested by inhalation for developmental effects in rats and mice. Evidence for intrauterine growth retardation was seen at an exposure concentration of 115 ppm (Bio/dynamics 1984a,b). At 150 ppm, exencephaly was seen in several fetuses. While the incidence of this malformation was not statistically significant, it was seen in both species and only in treated animals. Dose-related maternal toxicity was evident in all treatment groups. Isophorone has not been tested for developmental effects by the oral or dermal route. No studies were located demonstrating that isophorone crosses the placenta in animals or in humans, but there is no reason to assume that it does not do so. It is not known whether isophorone could cause developmental effects in humans. 

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