Air Pollution, the Automobile, and Public Health (1988) / Chapter Skim
Currently Skimming:
Assessment of Carcinogenicity: Generic Issues and Their Application to Diesel Exhaust
Assessment of Carcinogenicity: Generic Issues and Their Application to Diesel Exhaust
Pages 519-554
The Chapter Skim interface presents what we've algorithmically identified as the most significant single chunk of text within every page in the chapter.
Select key terms on the right to highlight them within pages of the chapter.
From page 519... ...
(it) 1988 by the Health Effects Institute.
|
From page 520... ...
Certain familial tendencies or acquired illnesses are also thought to predispose people to cancer. In this chapter, the evidence on the carcinogenicity of diesel engine exhausts and the methods used to make quantitative risk estimates from these data are evaluated.
|
From page 521... ...
This goal has been approached by undertaking culture studies of human cells and tissues obtained at immediate autopsies or from surgical specimens (Harris and Trump 1983~. Studying the properties of human tissues in vitro allows examination of the human diversity in cancer development.
|
From page 522... ...
Treatments of cells or animals with chemical carcinogens or radiation cause the onset of DNA repair processes. In studies in which cell proliferation has been inhibited and DNA repair has been allowed to remove some or most carcinogen-induced DNA adducts, the transforming effects of the carcinogen damage have been reduced (Ikenaga and Kaku naga 1977~.
|
From page 523... ...
Genetic EEects of Carcinogen Damage to DNA Point mutations transitions and transversions Frameshift mutations small deletions or additions Mutations at "hot spots" Chromosomal breakage at "fragile sites" Recombinations and rearrangements Sister chromatic exchanges Translocations of portions of chromosomes Gene amplification Aneuploidy DNA segments between sister chromatics, and chromosomal breakage that leads to large deletions or transposition of chromosomal segments to other chromosomes. Presumably, such damage may lead to failures of mitotic division with unequal distribution of chromosomes between daughter cells, resulting in abnormal DNA content.
|
From page 524... ...
Atypical Carcinogens A number of substances very different from the typical chemical carcinogens have been shown to be carcinogenic in humans and in experimental animals. With atypical carcinogens, carcinogenesis can be induced by physical agents and chemicals that do not directly alter DNA.
|
From page 525... ...
Exposure to carcinogens is not the only determinant of cancer development. Other substances or other processes can influence the risk for cancer development, particularly when they complement exposures to carcinogens or act on animals that have a high spontaneous tumor incidence.
|
From page 526... ...
A similar sequence of premalignant lesions of the bronchial epithelium precedes invasive lung cancer (Auerbach et al.
|
From page 527... ...
These studies first were successful in rodent embryo and fibroblast cells. More recently, similar results have been achieved using rodent epithelial cells, and in the past few years human cells have also been transformed with chemical carcinogens.
|
From page 528... ...
19764. It is likely that other genetically determined factors may influence cancer risks even if they do not yield recognized genetic diseases.
|
From page 529... ...
There has also been speculation that other lung conditions predispose people to lung cancer development (Kuschner 1985~. Although it is likely that these conditions predispose people to lung cancer because of increased cell proliferation rates, it is also possible that these conditions affect the capacity of the lung to clear exogenous materials, including potential environmental carcinogens.
|
From page 530... ...
This results in large rate differences in metabolism that correlate with the spectrum of distribution of tumors. Qualitative Assessments of Carcinogenicity Epidemiologic Evaluation The most powerful and convincing evidence for the carcinogenicity of a substance is the demonstration of its association with an excess of cancer in epidemiologic studies.
|
From page 531... ...
The extent of the increase in incidence and the strength of the statistical significance are used to weigh the importance of the relationship. In cases where there is good epidemiologic evidence linking an environmental exposure to cancer development and there are good quantitative data on exposure of the human subjects, it is possible to make reasonable predictions of the risks associated with future exposures at similar dose levels.
|
From page 532... ...
Cell proliferation, either constitutive or induced in response to injury, is an essential characteristic of tissues with a high risk of developing cancer. The information presented earlier indicates that cell proliferation, and in particular DNA synthesis, may have a crucial role in the various mechanisms of carcinogenesis.
|
From page 533... ...
Since the doses used to test for this activity are generally much higher than doses usually experienced by the human population, it is conceivable that toxicity may be a significant factor in tumor development. A chemical that tests positively in such a bioassay may require cell toxicity and the resulting increased cell proliferation of regenerative processes in order to evoke a tumor response.
|
From page 534... ...
Factors Involved in Quantitative Estimates of Human Risk Estimates of quantitative risk in experimental animals Extrapolation among species Extrapolations among routes of administration and exposure Extrapolation to dose levels of human exposure world" exposures to substances judged qualitatively to be carcinogenic are consid ered. In the event that sound epidemiologic evidence for carcinogenicity exists and adequate data on exposure rates in study populations are available, it may be possible to directly estimate cancer risks for humans.
|
From page 535... ...
In most cases, the route of administration is chosen for practical reasons: to simplify the methods of the study and to limit costs, not because of the similarity to the typical exposure route of the human population. Because long-term tests often involve routes of administration dissimilar to those of typical human exposure, methods have been developed to relate experimental results in animals to estimates of human cancer risk.
|
From page 536... ...
Although this approach offers a reasonable and pragmatic solution when practiced with adequate biological insight, its reasonableness does not ensure its correctness or accuracy, since it has not been adequately studied and validated by rigorous scientific tests. Even allowing for substantial safety factors in applying this method, it is unclear whether the conclusions generated are sufficiently protective or vastly too restrictive when used in extrapolations to human cancer risks.
|
From page 537... ...
Objective tests of the validity of the process of extrapolation by analogy must be undertaken. If the currently used extrapolation methods are precise or even reasonably effective, then they should be used to make testable estimates of human cancer risks, or, conversely, predict effects in experimental animals from human data.
|
From page 538... ...
It would point out the deficiencies of adoption of any general and universal extrapolation method for human cancer risk of all chemicals. The effects of small doses of carcinogens have been the subject of considerable conjecture, because of the absence of critical data concerning carcinogenic effects at very low doses and a still quite incomplete knowledge of the mechanistic details of carcinogenesis.
|
From page 539... ...
If these data were available for experimental and epidemiologic studies, it might be possible to predict cancer risks better, and these estimates of risks might be provided on an individual basis. With such information, it might be possible to monitor work conditions or even modify the design of internal combustion engines or their fuel, in order to minimize levels of harmful agents, or to reduce their levels to acceptable limits.
|
From page 540... ...
cells DNA adduct detection using the 32P-postlabeling technique Sister chromatic exchange in CHO cells Sister chromatic exchange in human lymphocytes treated in vitro Sister chromatic exchange in fetal hamster liver exposed transplacentally Cell focus transformation assay in SHE cells Cell focus transformation assay in BALB/c mouse 3T3 cells Short- Term Tests of Activity of Diesel Emissions Short-term in vitro assays that detect mutagenesis or other activities that suggest carcinogenic potential (table 6) have been used to evaluate diesel engine exhaust (Lewtas et al.
|
From page 541... ...
In the former study, cells were exposed to an organic extract of diesel exhaust particulates; in the latter study, hamsters were exposed transplacentally to exhaust emissions, exhaust particulate material, or to an organic extract of the particulates. In both studies the diesel exhaust extracts produced a dose-related increase in sister chromatic exchanges.
|
From page 542... ...
The carcinogenic activity of diesel engine exhaust was evaluated in a separate study using the lung adenoma in strain A mice as an end point (Orthoefer et al.
|
From page 543... ...
Quantitative Assessment of the Cancer Risk of Diesel Exhaust in Humans Some of the abovementioned studies have been used to assess the potential carcinogenicity of diesel engine emissions for the human population. Rather than the stepby-step extrapolation approach described earlier, the evaluation rested on earlier cal , .
|
From page 544... ...
To relate these values to estimates of risk for the human population, estimates of human lung cancer risk were made for coke oven emissions, roofing tar, and cigarette smoke condensate. For each of these compounds there were epidemiologic data relating exposure to human cancer and experimental data in test systems identical to that for diesel exhausts.
|
From page 545... ...
In view of the variability of diesel engine exhausts due to engine design, conditions of operation, and the fuel used, it is necessary to perform more studies to evaluate the influence of these variables on tumor responses. Exposure to diesel alone should be complemented by studies in which diesel exhaust exposures follow initiating carcinogen treatment in each of several organs or tissues.
|
From page 546... ...
Cancer development has come to be recognized as a slowly progressing, multifactorial, multistep process. Cell proliferation is known to have one or several roles in the process, and abnormalities of the control of this process are fundamental features of cancer cells.
|
From page 547... ...
The risk for diesel engine exhaust was calculated to be comparable to the approximate range found for other carcinogenic human exposures such as coke oven emissions and roofing tar. Within the limitations of these estimates, diesel engine exhausts do not appear to be notably more active than these other materials.
|
From page 548... ...
and gathering critical data for quantitative assessments (Recommendation 4~. By learning how to make quantitative risk assessments that account for effects of toxicity, and which involve extrapolations to low doses, among routes of administration, anc among species, In a manner more firmly founded on scientific knowledge, better estimates of human cancer risks in general will become possible, and this will benefit the assessments of diesel exhaust.
|
From page 549... ...
The following plan considers these different perspectives in defining a preferred set of priorities. HIGH PRIORITY No other organization will commit comparable attention or resources to the study of diesel engine exhaust, and therefore this must be done by the Health Effects Institute.
|
From page 550... ...
1983. Evaluating lung cancer risks from exposures to diesel engine exhaust, Risk Anal.
|
From page 551... ...
1982. Induction of sister-chromatic exchanges in human lymphocytes by extracts of particulate emissions from a diesel engine, Mutat.
|
From page 552... ...
1982. Effect of diesel exhaust emissions, particulates and extract on sister chromatic exchange in transplacentally exposed fetal hamster liver, Environ.
|
From page 553... ...
1986. Identification of DNA damage as a result of exposure of rats to diesel engine exhaust, Proc.
|
Key Terms
This material may be derived from roughly machine-read images, and so is provided only to facilitate research.
More
information on Chapter Skim is available.