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RQ13 - Name Key Due Fieview Questions — TODD Benzene...

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Unformatted text preview: Name: Key Due: Fieview Questions — TODD, Benzene, Formaldehyde 1. Assuming TODD is a pure tumor promoter, some scientists assert an acceptable daily intake (AD!) of TODD can be caiculated from the no adverse response ievel (NARL) in rodents and a safety factor. If the NARL for the rat (0.2 kg) is 0.2 ng/day, what is the ADI for the human (70 kg)? 0.2 ng x 70 kg x 1/100 2 0.7 ng/day = 700 pg/day = ADI 0.2 kg 2. Other scientists beiieve TODD must be treated as a complete carcinogen. (a) The ED50 for producing cancer in rats by TODD is approximately 20 ng/day. (Assume this is the only data point available.) In a iinear no threshold model, what daily dose would give rats a 10-6 chance of getting cancer (above background)? 100% cancer —> 2 x ED50 = 40 ng/day 40 ng/day x 10-5 z 40 x106 ng/day (b) On a weight basis, what would be the corresponding daily dose for humans? 10 kg x 40 x 10-6 ng/day = 14,000 x 10—6 ng/day = 14 pg/day 0.2 kg 3. Human TODD intake from "background" sources is estimated to be 50 pg/day. In View of your calculations above, do you think TODD is likeiy to play a significant role in the causation of "background" human cancer? Explain. Threshoid model : 700 pg/day > 50 pg/day > 14 pg/day = linear model Yes if (a) Humans are not dramaticaily less sensitive than rats, (b) TODD can promote carcinogenesis due to a variety of environmental agents to which we are ordinarily exposed, and (c) The threshold model is not valid. No it (a) Humans are much less sensitive than rats, (b) TODD is not an effective promoter for commonly encountered agents, or (c) The threshold model is valid. 4. Trace the pathway by which benzene is oxidized to 4,4‘~diphenoquinone. Why is this species (and others like it) toxic and a carcinogenic hazard? o c m— cacao i o~—»<:>=<:>:o a 0c, BmUnsaturated aldehydes and ketones are readiiy attacked by nuclephiles. This one can aiso give cross-linking. 5. Some investigators propose a dose dependence for leukemia from benzene shown roughly below. How could they rationalize the differences in marginal potency in the low, middle and high concentration regions? Low Mid High Low « DNA damage occurs but ceiis survive with mutations or chromosomal aberrations. Mid - Cell death occurs, giving rise to a regeneration response. Surviving damaged ceils are stimulated to divide more often, promoting neoplastic change. J High - The cytochrome P450 system is saturated, so the rate of Exposure electrophiie production increases little with increasing benzene. Leukemia 6. How do you think the general shape of the dose response curve for rodent cancer from formaldehyde compares with the proposed human curve above for benzene? Explain any major differences in shape. The formaldehyde curve resembles that for benzene in the tow and mid ranges. At the high end, the formaldehyde curve is very steep. One would not expect it to ievei off as in the benzene curve because formaldehyde does not need to be metabolized to be reactive. Thus, a plateau due to saturation of metabolism would not be expected. ...
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