Mammalian Toxicology Questions
Historical
Background of Toxicology (QS1Q1)
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?
Biochemical Kinetics (QS1Q2)
2. What information already discussed is subsumed in the
notion of biochemical kinetics?
Agencies & Risk (QS1Q3)
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?
Risk Assessment (QS1Q4)
4. What is risk assessment with
respect to humans, animals, ecology?
Assumptions from Animal Testing (QS1Q5)
5. What are the assumptions
underlying the use of animal testing in assessment of possible human toxicity
risks? Are they justified?
Chronic Toxicity & Carcinogenicity (QS1Q6)
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?
Toxin Metabolism Considerations (QS1Q7)
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?
Risk Approach: Cancer vs Reproduction (QS1Q8)
8. In risk assessment, is the approach used for evaluation of cancer risk
appropriate for reproductive or developmental risks?
Risk Models: Cancer vs Reproduction (QS1Q9)
9. Similar to 8. Are the same risk and test models
applicable to evaluation of cancer or reproductive and developmental risks?
Risk Strategies & Levels of Toxicity (QS1Q10)
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?
Food Safety (QS2Q1)
11. 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?
NOAEL, LOAEL & Threshold Model (QS2Q2)
12. 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?
PCBs & Thyroid Function (QS2Q3)
13. 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?
Repair Functions & Toxicity (QS2Q4)
14. 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?
Toxicology Information (QS2Q5)
15. 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?
Oral Toxicity Paradox (QS2Q6)
16. 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?
Phase I & II Metabolism (QS2Q7)
17. 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?
Temporal Changes in Toxicity (QS2Q8)
18. 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?
DNA Size (QS3Q1)
19. 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?
Gut Physiology (QS3Q2)
20. 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?
Macromolecular Chemistry (QS3Q3)
21. 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?
Time, Dose, Shielding (QS3Q4)
22. In radiation protection there
are three cardinal rules for minimizing radiation exposure:
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?
Portal Site Active Agent (QS3Q5)
23. 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?
Carcinogenesis Models. (QS4Q1)
24. 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?
Carcinogens and Risk Assessment. (QS4Q2)
25. 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?
Genetic Toxicology & Evolution (QS4Q3)
26. 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?
Genetic Toxicity: Possible Models? (QS4Q4)
27. 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?
Appropriate distinctions between carcinogenesis and genetic
toxicity? (QS4Q5)
28. 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
Cross System Enzyme
Induction (QS5Q1)
29. A number of endogenous compounds as well as xenobiotics cause induction of enzymes that apparently have no role in their own metabolism. Why might this make sense evolutionarily? Or, why might it simply be a relic of evolution within these metabolic systems? Provide specific examples, if possible, to defend your argument (or demolish someone else's).
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.