Chronic exposure, estimating dose

A report entitled Chemical Trespass was issued in May 2004 by the Pesticide Action Network (Schafer et al., 2006). It contained detailed analysis of 2000/01 National Health and Nutrition Examination Survey (NHANES) OP urinary metabolite data and used published methods to estimate exposure levels to parent compounds from creatinine corrected urinary metabolite levels. They focused on chlorpyrifos and its metabolite 3,4,6-trichloro-2-pyridinol (TCP), and found that chlorpyrifos exposures for children ages 6-11 and 12-19 exceeded EPA s chronic population-adjusted dose (cPAD) by surprisingly wide margins. Geometric mean TCP levels were 3 to 4.6 times higher than the EPA-estimated safe dose, as shown in Fig. 14.2. The more heavily exposed children received daily doses more than ten times the safe level. 

In intermediate-duration dietary studies with decaBDE, there was no exposure-related mortality in rats that were exposed to estimated dietary doses of < 90 mg/kg/day for 28 days (IRDC 1976) or rats and mice fed estimated doses of < 8,000 and < 9,500 mg/kg/day, respectively, for 13 weeks (NTP 1986). In chronic studies, there were no effects on survival in rats that were fed 0.01-1.0 mg/kg/day of a 77.4% decaBDE mixture (containing 21.8% nonaBDE and 0.8% octaDBE) for 2 years (Kociba et al. 1975 Norris et al. 1975b), or in rats and mice fed decaBDE in estimated doses of < 2,550 and < 7,780 mg/kg/day, respectively, for 103 weeks (NTP 1986). 

As an alternative to the assumption of a one-time exposure for 1,000 h at the time of facility closure, permanent occupancy of a disposal site following loss of institutional control could be assumed (see Section 7.1.3.4). The assumption of chronic lifetime exposure would affect the analysis for hazardous chemicals that induce deterministic effects only if estimated intakes due to additional pathways, such as consumption of contaminated vegetables or other foodstuffs produced on the site, were significant. Based on the results for lead in Table 7.8, an intake rate from additional pathways of about 50 percent of the assumed intake rate by soil ingestion, inhalation, and dermal absorption would be sufficient to increase the deterministic risk index above unity. The importance of additional pathways was not investigated in this analysis, but they clearly would warrant consideration. The increase in exposure time during permanent occupancy does not otherwise affect the analysis for chemicals that induce deterministic effects, provided RfDs are appropriate for chronic exposure, because chronic RfDs incorporate an assumption that the levels of contaminants in body organs relative to the intake rate (dose) are at steady state. 

All of the previously mentioned exposure methods can be used to estimate either chronic exposure (over a period of years) or acute exposure (single day) for the United States population and population subgroups. Both chronic and acute assessments are usually based on a no observed adverse effect level (NOAEL) in an animal species. Acute exposure is defined relative to an acute (single dose) toxicological endpoint (usually a NOAEL) and may be expressed as a margin of exposure (MOE) or as a percentage of an acute reference dose that is based on a NOAEL and an uncertainty factor (see below). 

Several assessments were conducted to illushate the impact of different procedures on dietary risk assessment. In all cases, consumption data from the UK surveys were used. One of the differences between the US and the EU is the food consumption data. However, conducting assessments with both US and UK food consumption data will confound the comparisons, so the assessments will be run using only the UK food consumption data. All exposure estimates are presented as percent of the chronic Reference Dose (cRiD) of 0.005 mg/kg bw/day or the acute Reference Dose (aRfD) of 0.01 mg/kg bw/day (both toxicity values are hypothetical for illushative purposes). 

In the West Indies especially, pyrrolizidine alkaloid toxicity is a continuing problem, as plants containing pyrrolizidine alkaloids such as Heliotropium, Senecio, and Crotolaria species are used in traditional medicine to make herbal teas. Chronic exposure to low doses of these alkaloids causes liver cirrhosis, and it is estimated that these alkaloids account for one-third of the cirrhosis cases detected at autopsy in Jamaica (see Chapter 6 for more details of these natural toxins). 

The strychnine oral reference dose (RfD) of 0.0003 mg/kg/ day or 0.02 mg/day for a 70 kg person is derived from the Seidl and Zbinden (1982) short-term to subchronic study by applying an uncertainty factor of 10,000. This factor accounts for extrapolation from a less than chronic to a chronic exposure study, extrapolation from animals to humans, and differences in sensitivity among the human population. An additional factor of 10 is used because an LOAEL/FEL (2.5 mg/kg/day) was utilized in the estimation of the RfD instead of an NOAEL. The immediately dangerous to life and health (IDLH) dose for strychnine by NIOSH REE is 0.15 mg/m and the current OSHA PEL is 0.15mg/m. ... 

Scientists then determine the appropriate uncertainty (or safety) factors to apply to the no-observed-adverse-effect level (NOAEL) or lowest-observed-adverse-effect level (LOAEL) for the critical effect, based on considerations of the available toxicity, toxicodynamic, and toxicokinetic data. Uncertainty factors (UFs) used in the estimation of safe doses are necessary reductions to account for the lack of data and inherent uncertainty in these extrapolations. Other areas of uncertainty include extrapolations of subchronic-to-chronic exposure, LOAEL to NOAEL, and use of an incomplete database. The major assumptions underlying each of these UFs are described in Table 1. 

Risks associated with the ingestion of contaminated dust have been estimated by Butte and Heinzow [85] using the chronic oral reference dose available from the US-EPA Integrated Risk Assessment Information Service [156]. With a focus on small children (age 1-6 years, mean body weight 16 kg) and a daily intake of 100 mg house dust [24,83] tentative benchmarks for house dust were calculated. The assessment indicated for chlorpyrifos, DDT and diazinon that the tolerable exposure concentration in house dust might be exceeded in some samples and chlorpyrifos especially can be considered a potential hazard to householders. 

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