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Environmental Protection Agency Washington, D.
Even if one could do such an experiment on peo- ple, the uncertainty in the doses and the possibility that the responses of individuals may vary greatly make such experiments more or less useless for risk assessment for the average person.
Using this important modification, studies in the s suggested that most carcinogens are mutagenic and conversely, that most non- carcinogens are nonmutagenic. The test is unambiguous, quantitative, sensitive, and rather simple. The of persons or person-years at risk should be sufficient seekig detect a statistically ificant difference in cancer rates between ex- posed and control subjects. An additional complication, hidden in the above analysis, is the implication that one knows which are the important activated compounds, and which are the important reaction products in macromolecules.
The answers to these questions emerged dramatically. The lethal effect of the lesion is circumvented, but a mutation occurs during the process.
Using Drosophila, Muller first devised a test to detect induced mutation. Setlow and Carrier and Boyce and Howard-Flanders showed that a dimer and some adjacent nucleotides are excised, and that a correct sequence of nucleotides is laid down in the resulting gap, using the comple- mentary chain as a template. An exception to this generalization is mammalian cell lines, which have a very limited ability to activate promutagens; therefore, when such cells are used as indicators, an S-9 fraction is added.
In fields in which short-term tests exist, the authors have critically reviewed their status, they have discussed how the tests might be more precisely defined and have pointed the way to future programs of research. Lifetime assays on animals do not readily lend themselves to routine testing because quality assurance is difficult over a two- or three-year period or more.
Gardner, and J. The most common photoproducts in cellular DNA are intrastrand pyrimidine dimers.
A second principle is that there are many ways that the genetic material can be al- tered, resulting in mutations. When a gamete that contains less or more than 23 chromosomes combines with a normal srafford, an aneuploid individual is produced. Genetics pursues an understanding of how biological traits are inherited, how information is encoded in the genetic material, and how this information is used in cells. Generation of Data It is very difficult in many cases to obtain data even if one is willing to accept the obstacles of endpoint definition and extrapolations.
If, instead, the sensitivity of xeroderma pigmentosum cells decreased to normal values at very low dose rates, the extrapolation would not be valid. Also, the assessment of the dose that an individual has received is difficult, since ex- posure estimates in retrospective epidemiological studies are usually not much better than an order of magnitude. At low doses of environmental agents, the effects of concern are either small ones, such as minor headaches, that affect large s of people or large ones, such as cancer, that affect small s of people.
Goth, D. With epidemiology of limited use and clinical studies for chronic effects not allow- able, we have to try to get the most we can from derived data from nonhuman test systems.
Recent vigorous challenges in court of assertions of the carcinogenicity of a substance based upon cancers or tumors induced in laboratory animals indicate that short-term tests will have to meet the above conditions at least as well as currently used long-term animal assays. Scully, S.
The background biological effect could arise from causes other than the specific adducts under consideration. Cells defective in nu- cleotide excision repair, such as uvrB mutants of Salmonella, must use other path- ways, at least one stoned which is error prone. Cornfield, J.
Second, it has been discovered that cells possess complex and amazingly effective enzymatic mechanisms for removing or bypassing certain of these lesions. Morgan showed that the mutant allele for white eyes is recessive to the wild-type allele for red eyes and is lo- cated on one of the sex chromosomes referred to as the X chromosome. The basic building blocks of DNA are nucleotides, which are covalently bonded together in a specific way to form a polynucleotide chain.
A mutation is an abrupt change in phenotype that is inherited, and a mutant is the individual resulting from such a change. Moreover, there are good indications in prokaryotic systems, and some in eukaryotic ones, that low chronic doses of alkylating agents may stimulate the production of a repair system to remove alkylguanine.
Hoel, D. The level of a pollutant that will be tolerated is very much influenced by what can be done about it. The problem of thresholds in chemical carcinogenesis. The growth of the chemical industry burgeoned after World War II, particularly the petrochemical industries. Although the incidence of cigarette smoking in males increased steadily from to saffordthe incidence of lung cancer did not show a similar increase staffofd 25 to 30 years later.
Comptroller General's Report to Congress. In humans, euploidy other than the diploid condition generally is lethal before birth, whereas some kinds of aneuploidy are compatible with life but usually cause severe mental and physical defects. A typical example is the effects arising from exposure to ionizing radiation. This means there is satfford tendency for regulations to be as stringent as possible considering the political pressure that increasing strin- gency generates.
Loss of a chromosome in humans usually is incompatible with life, except for monosomy 2N - 1 for the X chromosome 45,X. Pegg, A. Conferences on Cell Proliferation, Vol.
As data from mutagenicity tests accumulated in the s and s, mutagens were discovered among numerous classes of chemicals such as food additives, medicinals, pesticides, cosmetics, and industrial chemicals.
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