Human Equivalent Concentration

If an inhalation study in animals, list conversion factors used in determining human equivalent concentration NA... 

The resulting AEGL-3 values are shown in Table 3-11. Conversion of animal exposure data to human equivalent concentrations based upon minute volume and body weight relationships was not appropriate. Such a conversion predicted that monkeys and dogs would be more sensitive than rodents, a contention that is not supported by the animal data. Furthermore, the conversion to human equivalent concentrations assumes 100% absorption of inhaled monomethylhydrazine such absorption efficiency has not been verified. 

Used to derive an acute-duration inhalation minimal risk level (MRL) of 6 ppm. The NOAEL was converted to a Human Equivalent Concentration (HEC) of 181 ppm by multiplying by (0.22 mVday/0.204 kg), the reference value for Sprague-Dawley rats (EPA 1988a), and dividing by (20 nf/day/70kg), the reference value for humans (EPA 1988a). The HEC was divided by an uncertainty factor of 30 (3 to extrapolate from animals to humans, and 10 for human variability). 

Human Equivalent Concentration was calculated using default values from EPA (1988a). 

The MRL is based on a NOAEL of 0.5 mg/m3 for decreased acetylcholinesterase activity in rats exposed to disulfoton 4 hours/day for 5 days in a study by Thyssen (1978). The NOAEL was adjusted for intermittent exposure, converted to a human equivalent concentration, and divided by an uncertainty factor of 30 (3 for extrapolation from animals to humans and 10 for human variability). Inhibition of erythrocyte cholinesterase activity and unspecified behavioral disorders were observed at 1.8 mg/m, and unspecified signs of cholinergic toxicity were observed at 9.8 mg/m. Similar effects were observed in rats or mice exposed to higher concentrations for shorter duMtions (Doull 1957 Thyssen 1978). The NOAEL value of 0.5 mg/m is supported by another study, in which no significant decrease in the activity of brain, serum, or submaxillary gland cholinesterase was found in rats exposed to 0.14-0.7 mg/m for 1 hour/day for 5-10 days (DuBois and Kinoshita 1971). Mild depression of erythrocyte cholinesterase activity was reported in workers exposed by the inhalation and dermal routes (Wolfe et al. 1978). 

The intermediate MRL is based on a NOAEL of 0.02 mg/m3 for decreased acetylcholinesterase activity in rats exposed to disulfoton 6 hours/day, 5 days/week for 3 weeks in a study by Thyssen (1980). The NOAEL was adjusted for intermittent exposure, converted to a human equivalent concentration, and divided by an uncertainty factor of 30 (3 for extrapolation from animals to humans and 10 for human variability). In the Thyssen (1980) study, 2 separate 3-week experiments... 

Used to derive an acute-duration inhalation minimal risk level (MRL) of 0.1 ppm concentration is converted to a human equivalent concentration and divided by an uncertainty factor of 30 (3 for extrapolation from animals to humans and 10 for human variability). 

The MRL was based on a hepatic NOAEL of 3 ppm chloroform administered for 6 hours a day for 7 consecutive days to mice (Larson et al. 1994c). Female mice exposed to 100 or 300 ppm exhibited centrilobular hepatocyte necrosis and severe diffuse vacuolar degeneration of midzonal and periportal hepatocytes, while exposure to 10 or 30 ppm resulted in mild-to-moderate vacuolar changes in centrilobular hepatocytes. Decreased eosinophilia of the centrilobular and midzonal hepatocyte cytoplasm relative to periportal hepatocytes was observed at 30 ppm. Livers of mice in the 1 and 3 ppm groups did not differ significantly from control animals and were considered to be NOAELs for liver effects. The NOAEL of 3 ppm was converted to the Human Equivalent Concentration (HEC) as described in Equation 4-10 in Interim Methods for Development of Inhalation Reference Concentrations (ERA 1990b). This calculation resulted in a NOAEL hec] of 3 ppm. An uncertainty factor of 30 (3 for extrapolation from animals to humans and 10 for human variability) was applied to the NOAEL hec] value, which resulted in an MRL of 0.1 ppm. 

For dosimetry adjustment, the human equivalent concentration (HEC) is calculated based on aNOAEL of 3 ppm using Equation 4-10 (EPA 1990b). This equation was used due to the observation that chloroform achieves periodicity within 10% of the exposure duration (see Table A-1 below). Using Equation 4-10, the calculation is ... 

NOAEE jjec] = Human Equivalent Concentration of the NOAEL (no-observed-adverse effect level)... 

Equation 4-48a of EPA (1994k) was used to calculate the human equivalent concentration. 1,4-Dichlorobenzene is a category 2 gas however, the formula in the EPA (1994) document for extrarespiratory effects of category 2 gases is presently under review. Therefore, the equation used to derive this MRL is for category 3 gases. 1,4-Dichlorobenzene produces extrarespiratory effects (liver and kidney) and is expected not to obtain periodicity. A default value of 1 was used because the (Hb/g) / (H, /g)H values are not known. 

It is also noted that there is overlap in the individual UFs and that the application of five UFs of ten for the chronic reference value (yielding a total UF of 100,000) is inappropriate. In fact, in cases where maximum uncertainty exists in all five areas, it is unlikely that the database is sufficient to derive a reference value. Uncertainty in four areas may also indicate that the database is insufficient to derive a reference value. In the case of the RfC, the maximum UF would be 3,000, whereas the maximum would be 10,000 for the RfD. This is because the derivation of RfCs and RfDs has evolved somewhat differently. The RfC methodology (US-EPA 1994) recommends dividing the interspecies UF in half, one-half (10° ) each for toxicokinetic and toxicodynamic considerations, and it includes a Dosimetric Adjustment Factor (D AF, represents a multiplicative factor used to adjust an observed exposure concentration in a particular laboratory species to an exposure concentration for humans that would be associated with the same delivered dose) to account for toxicokinetic differences in calculating the Human Equivalent Concentration (HEC), thus reducing the interspecies UF to 3 for toxicodynamic issues. RfDs, however, do not incorporate a DAF for deriving a Human Equivalent Dose (HED), and the interspecies UF of 10 is typically applied, see also Section 5.3.4. It is recommended to limit the total UF applied for any particular chemical to no more than 3000, for both RfDs and RfCs, and avoiding the derivation of a reference value that involves application of the full 10-fold UF in four or more areas of extrapolation. 

Collectively, these studies adequately identify a LOAEL for respiratory effects associated with intermediate-duration inhalation exposure to chlorine dioxide. The intermediate-duration inhalation MRL for chlorine dioxide was based on the LOAEL of 1 ppm identified in the Paulet and Desbrousses (1972) study, which was adjusted to 0.15 ppm (LOAELadj) to compensate for intermittent exposure, converted to the human equivalent concentration (LOAELjjgc) of 0.3 ppm, and then divided by an uncertainty factor of 300 (3 for interspecies extrapolation using dosimetric adjustments, 10 for the use of a LOAEL, and 10 to account for sensitive populations). 

The human equivalent concentration (HEC) for the LOAEL (LOAELjjec) was calculated by multipl5ung the LOAELadj by the regional gas ratio for the pulmonary region of the respiratory tract (RGDRpu) according to the equation ... 

Approaches to duration adjustment are reviewed in Kimmel et al. (2006). Prior to derivation of NOAELs, LOAELs, or BMDs/ BMCs, the toxicity data are adjusted to a continuous exposure scenario. For oral studies, a daily exposure adjustment is made (e.g. a five days per week exposure is converted to seven days per week). For inhalation exposures, a concentration x time (c x t) adjustment is made. Traditionally, the inhalation exposure adjustment has not been done, because of concerns about peak versus integrated exposure and the likelihood of a threshold for effects. However, a review of the RfD and RfC processes by the USEPA recommended that inhalation developmental toxicity studies be adjusted in the same way as for other end-points (USEPA, 2002b). Derivation of a human equivalent concentration for inhalation exposures is intended to account for pharmacokinetic differences between humans and animals. 

Adjustments of NOAELs from inhalation exposure studies to a human equivalent concentration, based on adjustments for minute volume, respiratory rate, and other factors, are appropriate for reproductive and developmental toxicity (EPA 1994). Toxicity data are scaled directly from experimental animals to humans on the basis of minute volume per kilogram of body weight for inhaled materials and by weight (or volume) of the dose per body weight or surface area for other routes of exposure. The first priority is to use the internal dose at the target site, if available. 

Human equivalent concentration (HEC). The HEC is used to describe the dose of an agent to which humans are exposed through inhalation. The HEC is the estimated concentration that is equivalent to that used in an experimental animal species. The HEC is estimated using adjustment factors that account for such species-dosimetric differences as ventilatory parameters and lung surface areas, as well as factors related to the gas, aerosol, or particulate nature of the agent. 

The human equivalent concentration (HEC) was calculated using Formula 4-11, from Interim Methods for Development of Inhalation Reference Concentrations, EPA 1990h ... 

The adjusted animal NOAEL(adj) must be converted to Human Equivalent Concentration (LOAELhec) before applying uncertainty factors (UFs) adjustments (EPA 1994) for the derivation of the inhalation MRL ... 

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