home edit2 whole TSD November 2002 PDF format - OEHHA

Exposures expressed as mg/kg/day (m/Wr = s) are converted to mg/surface area using the relationship:
m
2 /3
= s * W
2/3
rW
The calculation of dose when exposure is via inhalation can be performed for cases where 1) the
chemical is either a completely water-soluble gas or aerosol and is absorbed proportionally to the
amount of inspired air, or 2) where the chemical is a partly water-soluble gas which reaches an
equilibrium between the inspired air and body compartments. After equilibrium is attained, the rate of
absorption is proportional to metabolic rate, which is proportional to the rate of oxygen consumption,
which is related to surface area.
Exposure expressed as mg/day to completely water-soluble gas or aerosols can be calculated using the
expression m = I * v * r, where I is the inspiration rate/day in m 3 , v is the concentration of the chemical
in air (mg/m 3 ), and r is the absorption fraction (assumed to be the same for all species in the absence of
data to the contrary; usually 1). For humans, the default inspiration rate of 20 m 3 has been adopted.
Inspiration rates for 113 g rats and 25 g mice have been reported to be 105 and 34.5 liters/day,
respectively. Surface area proportionality can be used to determine inspiration rate for rats and mice of
other weights; for mice, I = 0.0345 (W / 0.025) 2/3 m 3 /day; for rats, I = 0.105 (W / 0.113) 2/3 m 3 /day.
The empirical factors for air intake/kg/day (i) for humans, rats and mice are 0.29, 0.64 and 1.3,
respectively. Equivalent exposures in mg/surface area can be calculated using the relationship:
m
W = Ivr iWvr
= 2/3 2/3
W W = iW 1/3 vr
2/3
Exposure expressed as mg/day to partly water-soluble gases is proportional to surface area and to the
solubility of the gas in body fluids (expressed as an absorption coefficient r for that gas). Equivalent
exposures in mg/surface area can be calculated using the relationships m = kW 2 /3 * v * r, and d =
m/W 2 /3 = kvr. The further assumption is made that in the case of route-to-route extrapolations (e.g.,
where animal exposure is via the oral route, and human exposure is via inhalation, or vice versa), unless
pharmacokinetic data to the contrary exist, absorption is equal by either exposure route.
Adjustments are made for experimental exposure durations which are less than the lifetime of the test
*
animal; the slope q 1 is increased by the factor (L/L e ) 3 , where L is the normal lifespan of the
experimental animal and L e is the duration of the experiment. This assumes that if the average dose d is
continued, the age-specific rate of cancer will continue to increase as a constant function of the
background rate. US EPA states that age-specific rates for humans increase by at least the 2nd power
of the age, and often by a considerably higher power (Doll, 1971), leading to an expectation of an
increase in the cumulative tumor rate, and therefore q *
1 , to increase by at least the 3rd power of age.
If the slope q * 1 is calculated at age L e , it would be expected that if the experiment was continued for the
full lifespan L at the same average dose, the slope q * 1 would have been increased by at least (L/L e ) 3 .
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