Estimating Dose

To assess a carcinogen, doses are usually averaged over a lifetime and are presented as lifetime average daily doses (LADDs), even though exposure does not 

Although other measures of chronic dose may be more appropriate for predicting the hazard posed by specific chronic or carcinogenic toxicants, such as an area-under-the-blood-concentration (AUC) curve or the peak target tissue concentration, the LADD is the most common dose metric used in carcinogen risk assessment (Paustenbach and Madl 2008). 

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FIGURE 6.19 Use of the clextral displacement produced by an insurmountable antagonist to estimate dose ratios and subsequent pA2 values. Response according to model for orthosteric noncompetitive blockade (Equation 6.31 with Emax = 1, t = 3, Ka = 0.3 pM, Kb = 1 pM) for 1 pM and 3 pM antagonist. Dose ratios measured at response = 0.24 for 1 pM antagonist and response = 0.15 for 3pM antagonist. Resulting pA2 values are close estimates of the true pKB (6.0) as modified by the [A]/Ka term (see Equation 6.37). 

A 50-year-old white male died after intentional methyl parathion ingestion (Wofatox liquid) (Fazekas and Rengei 1964). The estimated dose of methyl parathion was 1,840 mg. Gross necropsy findings consisted... 

Three studies examined the effects of endosulfan exposure on reproductive performance in rats. Consumption of estimated doses of endosulfan of up to 9 and 8 mg/kg/day by male and female rats, respectively, for 2 weeks prior to mating and continued consumption throughout gestation resulted in no adverse effect on mating performance, pregnancy rate, or gestation (Hoechst 1982). This study is limited in that the actual intake of test material was quantified only during the first 2 weeks of exposure, and a relatively small number of animals was used. Similarly, consumption of 5 mg/kg/day by male rats and... 

The granular turf study was handled in a manner very similar to the liquid turf study discussed above. As might be expected, the estimated doses of chlorpyrifos for nine volunteers were considerably lower than the estimated doses in the liquid study. The volunteers chlorpyrifos doses ranged from 0.31 pg/kg to 0.44 pg/kg using physical measurements average 0.36 pg/kg. Utilizing analysis of urine, the average dose was estimated to be 1.3 pg/kg (Table 6). 

Table 5 Liquid Turf Study Estimated Doses of Chlorpyrifos Based on Biomonitoring and Physical Measurements...

Weanling female rats exposed to 250 ppm lead acetate in the water for 10 days exhibited an approximately 19% decrease in body weight gain during the exposure period (Minnema and Hammond 1994). This concentration of lead in the water provided an estimated dose of 17.5 mg lead/kg/day and doubled the blood ZPP levels in the treated rats. As indicated below, the reduced growth was due to a decrease in food intake, which in turn was due to a reduction in feeding time. 

It is important to remember that absolute oral bioavailability is a function of both absorption and first-pass metabolism. Therefore, a linear approach to predicting absolute oral bioavailability based on a single parameter, such as rate or extent of absorption (fraction of dose absorbed or estimated dose absorbed) or the rate of metabolism (microsomal or hepatic intrinsic clearance), may result in an inaccu-... 

Acute biological effects of the Chernobyl accident on local natural resources were documented by Sokolov et al. (1990). They concluded that the most sensitive ecosystems affected at Chernobyl were the soil fauna and pine forest communities and that the bulk of the terrestrial vertebrate community was not adversely affected by released ionizing radiation. Pine forests seemed to be the most sensitive ecosystem. One stand of 400 ha of Pirns silvestris died and probably received a dose of 80 to 100 Gy other stands experienced heavy mortality of 10- to 12-year-old trees and up to 95% necrotization of young shoots. These pines received an estimated dose of 8 to 10 Gy. Abnormal top shoots developed in some Pirns, and these probably received 3 to 4 Gy. In contrast, leafed trees such as birch, oak, and aspen in the Chernobyl Atomic Power Station zone survived undamaged, probably because they are about 10 times more radioresistant than pines. There was no increase in the mutation rate of the spiderwort, (Arabidopsis thaliana) a radiosensitive plant, suggesting that the dose rate was less than 0.05 Gy/h in the Chernobyl locale. 

Populations of soil mites were reduced in the Chernobyl area, but no population showed a catastrophic drop in numbers. By 1987, soil microfauna — even in the most heavily contaminated plots — were comparable to controls. Flies (Drosophila spp.) from various distances from the accident site and bred in the laboratory had higher incidences of dominant lethal mutations (14.7%, estimated dose of 0.8 mGy/h) at sites nearest the accident than controls (4.3%). Fish populations seemed unaffected in July/August 1987, and no grossly deformed individuals were found. However, 34+ i 37( s levels were elevated in young fishes. The most heavily contaminated teleost in May 1987 was the carp (Carassius carassius). But carp showed no evidence of mutagenesis, as judged by incidence of chromosomal aberrations in cells from the corneal epithelium of carp as far as 60 km from Chernobyl (Sokolov et al. 1990). 

Developing forebrain, 0.18-0.55 Gy (estimated dose to prenatally exposed Japanese atomic bomb survivors) Seizures in childhood reduced school performance at least through age 11 years some cases of severe mental retardation by age 17 years 12... 

It is unlikely that a victim of a terrorist attack will use the information in Table 3.2. This information may, however, be useful to emergency responders and medical personnel during triage to identify the most highly exposed individuals. The information may also be useful to postattack investigators who must reconstruct the crime scene and estimate doses to all potential victims. 

Hepatic Effects. Serum markers of liver effects, bilirubin, glucose, cholesterol, and aspartate aminotransferase were not affected in 39 persons exposed to phenol in the drinking water at an estimated dose of 0.14-3.4 mg/kg/day for several weeks (Baker et al. 1978). Because these examinations were completed 7 months after the spill, this study does not provide conclusive evidence that there was no reversible liver damage. 

Dermal exposure also occurs through the use of phenol-containing ointments, ear and nose drops, analgesic rubs (Douglas 1972), and antiseptic lotions (Musto et al. 1977). It is not possible to estimate dose levels for these sources given the available data. 

Tumors were not observed in male rats treated with 19 mg/kg/day doses of 1,2-diphenylhydrazine in the diet for life (mean survival time = 288 days) (Marhold et al. 1968). The significance of this finding is uncertain because the type and scope of pathological examination were not reported. Pliss (1974) reported increased numbers of tumors of the liver, Zymbal s gland, mammary gland and other sites in rats that were treated with 1,2-diphenylhydrazine in the diet at an estimated dose of 85 mg/kg/day, 5 days/week for 588 days (Pliss 1974). These findings are inconclusive, however, because of lack of control data and other report inadequacies. 

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