Mammalian Toxicology Questions Asked as of 2/21/03:

Already Asked

Question Set 1. Question 1. Questions arising from the historical background of toxicology.

1. The idea of causality arose during the middle ages and Renaissance. This builds on careful observation and testing. How might this give rise to the notions of occupational hazards or the nonmystical explanation for oncogenesis?

2. What information already discussed is subsummed in the notion of biochemical kinetics?

Question set 1. Question 6. Chronic Toxicity & Carcinogenicity

6. Note the emphasis of chronic toxicity testing and mutagenesis testing on carcinogenesis. Is this emphasis currently appropriate, or are there other possible chronic outcomes to be concerned with?

Question Set 1. Question 7. Toxin Metabolism Considerations

7. Emphasis in the discussion of biochemical and physiological means of toxin metabolism and clearance is on the adult animal. Are there other important considerations or routes to be considered in growing offspring or during the reproductive process?

Question Set 1. Question 10. Risk Strategies & Levels of Toxicity

10. What distinctions might be made between lethality, morbidity, reproductive capacity, quality of life, and quality of environment impacts vis a vis risk assessment strategies?

Question Set 2. Question 6. Oral Toxicity Paradox

6. Oral toxicity studies have defined a paradox of this route of exposure. What is the paradox and how might it be explained? A somewhat similar paradox can arise if dietary insoluble fiber is high and exposure is again oral. Why might this occur? Are either of these situations of possible use in treating acute poisonings? In chronic intoxications?

Question Set 3. Question 4. Time, dose, shielding.

4. In radiation protection there are three cardinal rules for minimizing radiation exposure:

1. minimize time of exposure to the source

2. maximize distance from the source to minimize dose delivered

3. optimize the amount and type of shielding used to minimize dose delivered.

Can these be translated into considerations in toxicant exposure? What are the analogs of time, dose, and shielding for chemical exposures? Are there any differences among routes of exposure or nature of toxicant that need to be considered?

Assignments for Session 3: Journal Citations

1. Provide at least 3 citations gleaned from articles in the toxicology journals posted.

Assignments for Session 3: Calcium Controls

2. Describe the control circuit for parathyroid hormone, calcitonin, and cholecalciferol; how would a blocker of 1[alpha]-hydroxylase impact calcium deposition in bone?

Assignments for Session 3: Project Ideas

3. Generate a list of 3 possible case studies for possible use in the course project; associate them with an article, Website, or other document that justifies possible interest in them.

Not Yet Asked

Question set 1. Question 3. Agencies & Risk

3. Modern toxicology includes the concepts of causality, risk assessment, and site specificity of action. Why are all these concepts relevant to the following agencies: USPHS, NSC, EPA, FDA, OSHA, NRC? How many of these agencies derive directly from concerns about toxicant exposures?

Question Set 1. Question 4. Risk Assessment

4. What is risk assessment with respect to humans, animals, ecology?

Question Set 1. Question 5. Assumptions from Animal Testing

5. What are the assumptions underlying the use of animal testing in assessment of possible human toxicity risks? Are they justified?

Question Set 1. Question 8. Risk Approach: Cancer vs Reproduction

8. In risk assessment, is the approach used for evaluation of cancer risk appropriate for reproductive or developmental risks?

Question Set 1. Question 9. Risk Models: Cancer vs Reproduction

9. Similar to 8. Are the same risk and test models applicable to evaluation of cancer or reproductive and developmental risks?

Question Set 2. Question 1. Food Safety

1. What steps are required for drug product clearance by the FDA? How are food supplements handled by the same agency? Are there additional or alternative rules for genetically engineered foods or drugs produced by genetically engineered organisms? Do such rules seem adequate to assure safety of humans using genetically engineered organisms or products? What about environmental safety of these organisms or products?

Question Set 2. Question 2. NOAEL, LOAEL & Threshold Model

2. Are the concepts of NOAEL and LOAEL most compatible with a threshold level or a no threshold level conception of dose responses? How are they represented on dose-response curves? How do they differ from zero dose? Does the last answer change for environmental exposures if newer methods allow lower limits of detection for the toxicant in question?

Question Set 2. Question 3. PCBs & Thyroid Function

3. Exposures to PCBs can potentially alter thyroid function in part because of the structural similarities of some of the PCB isomers and thyroxine or triiodothyronine. About 50% of thyroxine is carried in circulation by thyroid binding globulin, TBG, while 45+% is carried by albumin or transthyretin. Much of thyroxine enters cells by diffusion, but a substantial quantity also enters via the aromatic amino acid transport proteins in cell membranes. After cell entry, thyroxine is deiiodinated to triiodothyronine which then binds to receptors that usually reside on DNA binding sites within the nucleus; binding often results in release of the hormone receptor complex from DNA and in a change in DNA structure and transcriptional activity. What are the obvious possible targets for PCB toxic effects? If we include molecular clearance pathways, are there other targets? What if the toxicant is a slightly acidic derivative of a PCB? What about an amine derivative of a PCB?

Question Set 2. Question 4. Repair Functions & Toxicity

4. How do repair functions complicate the analysis of toxicity in acute exposure models? What about chronic exposure models? Do they have the same impact on results in adults as opposed to developing animal models?

Question Set 2. Question 5. Toxicology Information

5. Search out the following sites and explore them: HazDat, EXTOXNET, RTECS, Toxline, IRIS, IARC. What information do they contain? Do they appear up to date? Print out some examples of the contents and see if you can interpret them. To what area(s) of toxicology are each of them relevant?

Question Set 2. Question 7. Phase I & II Metabolism

7. Generate two tables summarizing the components of Phase I and Phase II biotransformations involved in chemical metabolism and clearance. Note any specialized locations of any enzymes involved and the overall outcomes of the various steps in processing. If possible, include indications of the genes coding for the gene products involved. With the tables in hand, are there gross differences between these two phases of metabolism? What are they?

Question Set 2. Question 8. Temporal Changes in Toxicity

8. Given an increased knowledge of the metabolic pathways utilized by mammals to process toxicants, how would you now design an experiment in which two neuroactive drugs were to be used repeatedly to test particular brain circuits? Would any of this make any difference to your interpretation of results in which there was an apparent decline with time in the responsiveness to one of the drugs? Does this knowledge make you view the use of multiple drugs in elderly patients any differently?

Question Set 3. Question 1. DNA size

1. Look up the dimensions for 1 base pair of DNA and calculate the length of 1 complete copy of cellular DNA (3 x 10^9 base pairs). Compute the volume of a typical cell nucleus, about 10 um (10 x 10^-6 m) in diameter. How often does the DNA have to be folded to fit in that volume?

Question Set 3. Question 2. Gut physiology

2. The gut physiology of various mammals differs in ways that make oral intoxication of one species potentially very different from oral intoxication in another species. Look up the comparative gut physiology for as many mammalian species as possible. Note differences in the sizes of the stomach, the length and nature of the small intestine, the presence or absence of a caecum and its size, the length and size of the large intestine and colon. How might pure glucose ingestion affect a ruminant? A hindgut fermenter like a horse? Are there key differences among species that will define which toxicants will be more or less potent or efficacious in going from one species to another? Are the test species (rat, dog, mouse, rhesus) most commonly being used good models for humans? Or for other, wild species?

Question Set 3. Question 3. Macromolecular chemistry.

3. What are the chemical structures of cellulose, hemicellulose, pectin, glycogen, lactose, and sucrose? Does this list contain the principle forms of dietary insoluble fiber or are there others besides the silicates and minerals, that contribute?

Question Set 3. Question 5. Portal site active agent.

5. In the compartmental models of pharmacokinetics much emphasis is placed on distributional volume and the role of toxicant sinks and sources within tissues. Route of exposure plays an important role as dose mode of elimination. What happens to these models and considerations if the agent is active within the tissues where it is introduced? For example, how do we deal with a compound that acts on the lung if it is introduced as an aerosol?

Question Set 4. Carcinogenesis Models.

Given the discussion provided in the lecture alongside that provided by Casarett and Doull, are compounds that are listed as carcinogens that merely promote cell growth under normally encountered levels (as opposed to the elevated levels that might be provided during a carcigenicity test)really carcinogens? How many of these exist in the watch list for carcinogenic compounds? Does this distinction between growth promoters and overt carcinogens matter?

Question Set 4. Carcinogens and Risk Assessment.

The statement is made in Klasssen & Watkins III, Companion Handbook for Casarett & Doull's Toxicology, 5th Ed. (p 189) that: "For risk analysis, it is assumed that cancer induction differs from all other toxicological events in that the induction of cancer is a nonthreshold phenomenon or an accumulation of many such irreversible events." Is this justified mechanistically?

Question Set 4. Genetic Toxicology & Evolution

If pyrimidine dimers and chemical adducts to DNA are preferentially removed in transcribed and active DNA sequences relative to untranscribed and inactive DNA sequences, what does that suggest about the hot spots for genetic drift upon which evolution is based? If you were looking for gene sequences to use to differentiate among related species, what kind of genes would you tend to look at as indicators?

Question Set 4. Genetic Toxicity: Possible Models?

Why might the Plains Viscacha of South America be a good model for toxicity associated with oogenesis? Could the DAZ1 gene found on the long arm of the Y chromosome be used as a screen for germ cell toxicity in the primate male? How might the latter be evaluated?

Question Set 4. Appropriate distinctions between carcinogenesis and genetic toxicity?

Although cancer can arise in germline cells, it happens with higher frequency in other cell lines, i.e., it tends to be a problem arising primarily in somatic tissues. On the other hand, the vast majority of postfertilization losses during gestation and the inherited diseases linked to DNA mutations or chromosomal anomalies are the results either of inheritance via germ cell lines or due to genetic damage occurring during meiosis. It seems that lumping these two very different types of conditions together under the rubric of genetic toxicology or genetic toxicity confuses a number of issues with respect to the mechanisms by which the conditions arise and the impacts these changes have on individuals and populations. I suggest that it is probably better to speak of somatic cell genetic toxicity and germ cell genetic toxicity than to hold with the current dichotomy of carcinogenesis and genetic toxicity. Do you agree or disagree? Why or why not? What evidence can you marshall to support your position?