Methods for Developing Spacecraft Water Exposure Guidelines (2000) / Chapter Skim
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Appendix B Benchmark Dose Estimation
Appendix B Benchmark Dose Estimation
Pages 131-148
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From page 131... ...
In the 2-yr study, 1,4-dichlorobenzene was administered by Savage 5 d/wk at 150 and 300 mg/kg/d for male rats and at 300 and 600 mg/kg/d for female rats. The results of these studies are used below to illustrate the way to calculate BMDs for nonquantal response data, quantal data that are highly variable, and for carcinogenic effects (Table Bob.
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133 s J~ ,, ~ is' ,~z ~ i'; o P Cal o ho to ~ ¢ O Z ¢ ~0 CN ¢ o ¢ O ho U
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From page 134... ...
Figure B-4 gives similar information for the body weight gain data. BMDo~ and BMD~o for decreased hemoglobin concentration, decreased RBC count, and decreased body weight gain are all in close agreement.
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From page 135... ...
and BMD~o (334 mg/kg) are higher than the corresponding BMDp for other hematotoxic effects and for decreased body weight gain.
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Highly Variable Quantal Data The second 13-wk study of 1,4-dichlorobenzene identified a NOAEL of 150 mg/kg in male rats, based on renal tubular degeneration, which
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From page 137... ...
There was no increase in severity at 150 mg/kg, and because of the numerically lower incidence compared with the vehicle control, this was considered a NOAEL. A probit log-dose mode} was fitted to the incidence data, and a goodnessof-fit test indicated a marginally acceptable fit ~ = .07~- the fitted
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From page 138... ...
However, because of the high variability in the data that describe the dose-response relationship as shown in Figure B-5, convergence of the maximum likelihood estimation procedure could not be achieved for calculating lower CEs on doses corresponding to the specified excess risks of 1% and 10% (BMDo~ and BMD~o)
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From page 139... ...
However, the BMDo~ and BMD~o are reasonably close to the corresponding values calculated for the three hematology end points and decreased body weight gain (Table Bob. Carcinogenic Effects NIP found clear evidence of carcinogenicity in the 2-yr study.
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From page 140... ...
It should be noted that the cancer BMDo, of ~ mg/kg produced by the multistage mode} can easily be related back to EPA's cancer potency factor of 2 x Jo-2, assuming linearity of the dose-response curve at low doses. To define the potency factor, one must adjust ~ mg/kg to account for the discontinuous exposure regimen used In the study by multiplying by 5/7 (dosing was done 5 d/wk)
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From page 141... ...
For renal tubular degeneration, because of the ad hoc way the lower CL were calculated, it is easy to see that the ratio for BMDo~ is at least 2-fold higher than the ratio for BMD~o (449/72 = 6.2 versus 494/190 = 2.6~. For hepatocellular tumors, the ratio for BMDo~ is 3-fold higher than the ratio for BMD~o (e.g., multistage model: 56/S = 7.0 versus ISI/77 = 2.3~.
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From page 142... ...
DERIVING BMDS FOR BOTUEINUM TOXIN, VINYL CHLORIDE, AND AFLATOXIN Data on one toxic end point from botulinum toxin (lethality) , viny} chloride (liver tumor)
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was used to fit the botulinum toxin data in Table B-2 (Food Safety Council 1980) , assuming a background response level of zero.
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144 ·$ x o I; ·s x o EM g no CD o no o-O To ¢ O Z d i, - ~ 3 ~ C ~ C ~ C ~ |
From page 145... ...
This case illustrates one advantage of using BMDp instead of NOAEL, that is, no subjective judgment is needed to determine precisely which experimental dose is a NONES. Rather, fining a model to the dose-response data enables estimation of any dose as a BMDp.
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From page 146... ...
|BD (257) Figure B-9: Probit log-dose model of liver tumor data on vinyl chloride A probit {og-dose mode} was fitted to the aflatoxin Be data in Table B-2 (Food Safety Council 1980)
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From page 147... ...
predicts a nonzero background rate of approximately 5%, even though the observed background rate is zero. Although the data are quite variable at low doses, they are consistent with a nonzero background rate, and the mode!
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From page 148... ...
1993. Upper confidence limits on excess risk for quantitative responses.
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