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F Perera

Publications and source records attributed to F Perera.

34 records · Page 2Linked to original sources
PubMed1991

DNA adducts and other biological markers in risk assessment for environmental carcinogens.

In order to validate a number of biologic markers as indicators of effective dose or potential risk, we have applied them in related cross-sectional, longitudinal and case-control studies. Biologic markers such as carcinogen-DNA adducts and activated oncogenes have already provided insights into mechanisms of chemical carcinogenesis. They have also given information regarding the extent of interindividual variation in biologic response within the human population. These results are directly relevant to quantitative risk assessment. However, more research is needed to establish quantitative links between biologic markers and human risk of cancer.

Biomarkers↗
PubMed1990

Protein binding, sister chromatid exchange and expression of oncogene proteins in patients treated with cisplatinum (cisDDP)-based chemotherapy.

The aim of this pilot was to evaluate the feasibility of incorporating several complementary biologic markers into a molecular epidemiologic study of chemotherapy patients. Thirty-two cancer patients being treated with cis-DDP-based chemotherapy for the first time were enrolled in the study and donated a baseline sample and at least one post-treatment sample of blood. Sister Chromatid Exchange (SCEs) and plasma protein and hemoglobin binding by cisDDP were significantly increased in samples drawn at various timepoints following treatment. The pattern of nine different oncogene protein products (including those of ras, fes, and myc) remained unchanged in sera of six patients followed over the course of their treatment. However, the levels of ras P21 product were significantly elevated above normal, control levels in all six cancer patients--both prior to and throughout the course of chemotherapy. These results suggest the usefulness of utilizing a battery of markers to evaluate biologic response to cisplatinum-based chemotherapy.

Aged↗
PubMed1990

Macromolecular adducts and related biomarkers in biomonitoring and epidemiology of complex exposures.

In order to evaluate the potential of biological markers in epidemiology and risk assessment of complex exposures, we review recent studies of macromolecular adducts and oncogene activation in human populations. Results are discussed in terms of the strengths and weaknesses of various study designs in order to identify the most promising approaches for future research.

Biomarkers, Tumor↗
PubMed1989

Comparison of DNA adducts and sister chromatid exchange in lung cancer cases and controls.

In a molecular epidemiological study of lung cancer cases (n = 81) and noncancer controls (n = 67), polycyclic aromatic hydrocarbon (PAH)-DNA adducts were evaluated in peripheral blood leukocytes from all subjects and in a smaller number of lung tissue specimens collected prior to or at surgery. Sister chromatid exchanges (SCE) in lymphocytes were also studied in a subset of cases and controls. Questionnaire, medical record, or tumor registry data provided a family history of cancer, as well as information on cigarette smoking, dietary and occupational exposure to PAHs, and other factors related to SCEs. In both cases and controls PAH-DNA adducts in leukocytes measured by an enzyme-linked immunosorbent assay were not significantly related to age, sex, ethnicity, amount of cigarette smoking, passive smoking, dietary charcoal, or caffeine consumption. Nor did family history of cancer or histological type of cancer significantly affect adduct levels. However, when subjects were stratified by smoking status (current, former, and nonsmoker), lung cancer cases who were current smokers had significantly higher levels of covalent adducts than current smoker controls. A seasonal variation was observed in PAH-DNA binding, with a peak in adduct levels during July-October. This peak corresponds to that seen in a prior study of aryl hydrocarbon hydroxylase inducibility by other investigators. The finding of significant levels of PAH-DNA adducts in former smokers and non-smokers supports an earlier observation that this marker is not smoking specific but reflects a pervasive and variable "background" exposure to PAH. These results are consistent with a genetically determined enhancement of PAH-DNA adduct formation in leukocytes of lung cancer cases which is evident in current smokers. The results in lung tissue are limited by the small number of samples. Adduct levels were not significantly increased in lung tissue of smokers compared with nonsmokers. An inverse linear correlation was seen between adduct values in lung tissue and age of the donors. SCEs were significantly related to pack years of smoking. However, there was no difference in the frequency of SCE between cases and controls; nor were SCE and DNA adducts significantly correlated in this small sample.

DNA, Neoplasm↗
PubMed1989

Comment on the significance of positive carcinogenicity studies using gavage as the route of exposure.

There is continuing controversy, extending into regulatory matters, over the significance to human health of positive results in carcinogenicity studies in animals using the gavage technique as the route of exposure. Our review of a nonrandom sample of 117 chemicals or chemical processes listed as known or reasonably anticipated to be carcinogenic in the National Toxicology Program's Third Annual Report on Carcinogens provides support for the validity of the gavage route in such studies. Twenty-three chemicals among the 117 substances and processes listed were positive by gavage. Twenty of these 23 chemicals were also appropriately studied by at least one other route of exposure. Thus, we were able to evaluate the extent to which positive gavage results were confirmed by another route of exposure in this sample. Nineteen (or 95%) of the twenty chemicals were positive for carcinogenicity by at least one other nongavage route in carcinogenicity bioassays. Moreover, in each of these 19 cases, positive carcinogenesis results were obtained by a nongavage route in the same species of animal where gavage administration led to the induction of cancer. All of the 23 gavage-positive chemicals induced tumors distal to the site of administration in at least one study, as did all 15 chemicals which were also positive by subcutaneous injection. We emphasize, however, the limited scope of our survey. We have not evaluated all chemicals that have tested positive by gavage and by at least one alternative route, nor have we assessed those chemicals found to be negative by the gavage route.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1988

Perspectives of comparing risks of environmental carcinogens.

In 1987, investigators (Ames et al.) concluded that the risks of man-made industrial carcinogens and pesticides (outside of the workplace) are trivial compared with the risks of naturally occurring carcinogens found mostly in the diet. They used a ranking system based on human exposure and rodent potency (HERP) data to arrive at this conclusion. As a result, they recommend that regulatory agencies, such as the Environmental Protection Agency and the Food and Drug Administration, base their priorities in this area on their HERP system. We analyzed the assumptions and data set upon which the HERPs were based, concluding that such a simplified approach to set public health policy is inappropriate given the underlying uncertainties. However, we note that when comparisons are consistently based on estimates of average daily exposure to common carcinogens, the HERP scores of many man-made pollutants are comparable to those of naturally occurring carcinogens in the diet.

Carcinogens, Environmental↗
PubMed1987

The potential usefulness of biological markers in risk assessment.

Substantial data have been generated during the last 5 years in experimental systems and human populations which shed light on the potential usefulness of biological markers in human cancer risk assessment. Following a brief review of overall progress to date in the biomonitoring of human populations, this paper turns to the growing body of data regarding carcinogen-DNA and protein adducts as illustrative markers of biologically effective dose of carcinogens. The data base illustrates considerable human inter-individual variation in binding and the presence of significant "background" levels of adducts--both of which support the absence of human population thresholds for exposure to carcinogens. The contribution of adduct data to our understanding of the shape of low dose-response curve and the reliability of inter-species extrapolation, as well as the relevance of adducts to cancer risk, are also discussed. Even though adducts can now be useful in hazard identification or qualitative risk assessment, more research is needed before they can serve as quantitative predictors of human cancer risk.

Biomarkers, Tumor↗
PubMed1986

Immunologic quantification of carcinogen-DNA adducts.

Sensitive immunological methods for the detection of carcinogen-DNA adducts have recently been developed. These techniques are particularly useful for screening human populations for exposure to environmental carcinogens. Measurement of the biologically effective dose in humans may be useful in detecting carcinogenic hazards and carrying out risk estimates. We have developed monoclonal antibodies to several carcinogen-DNA adducts. These have included DNA modified by a benzo[a]pyrene diol epoxide (BPDE-I), 1-aminopyrene (1-AP) and 8-methoxypsoralen (8-MOP). BALB/cCr mice were immunized with the modified DNAs complexed electrostatically to methylated bovine serum albumin. Several stable clones have been isolated for each of the modified DNAs and characterized by enzyme-linked immunosorbent assay (ELISA). All antibodies are highly specific for the appropriate modified DNA and do not cross-react with nonmodified DNA. The antibodies to BPDE-I-DNA have significant cross-reactivity with DNAs modified by similar antitrans diol epoxides of benz[a]anthracene and chrysene. These DNAs all contain N-2 of guanine adducts. The antibody probably recognizes a shared determinant encompassing the guanine base and the hydrocarbon ring containing the hydroxide groups. The antibodies cross-react with BPDE-I-dG, the monoadduct isolated from DNA, but with lower sensitivity than for the intact modified DNA. They do not react with acetylaminofluorene (AAF) or 1-AP modified DNA, both of which contain C-8 of guanosine adducts. The antibodies to 1-AP-modified DNA demonstrate cross-reactivity with 8-nitro-1-aminopyrene- and 6-nitro-1-aminopyrene-modified DNA, as well as some slight cross-reactivity with BPDE-I-DNA and AAF-DNA.(ABSTRACT TRUNCATED AT 250 WORDS)

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗
PubMed1986

Biomonitoring of workers exposed to carcinogens: immunoassays to benzo(a)pyrene-DNA adducts as a prototype.

A new tool for the study of occupational carcinogenesis is "molecular dosimetry" or biomonitoring to establish the biologically effective dose of carcinogens in workers. Human monitoring of biologically effective dose and preclinical response has the potential to flag the need for protective measures and/or surveillance. Comparable biologically effective dose and preclinical response data in humans and laboratory animals for whom tumor incidence is known can also enhance risk extrapolation between species. This paper will provide a brief overview of biomonitoring methods now under development, including advantages, limitations, applications to date, and research needs. Application to the monitoring of worker populations requires careful thought about the use to which monitoring data will be put.

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗
PubMed1986

New approaches in risk assessment for carcinogens.

Methods are needed to improve the ability of biomonitoring and epidemiological studies to identify potential carcinogenic hazards and to quantify human risk. The limitations of pharmacokinetic models can be mitigated by the direct measurement of molecular markers of biologically effective dose of carcinogen. Parallel animal and human studies are recommended as a means of validating these markers.

Animals↗
PubMed1982

Formaldehyde: a question of cancer policy?

This article describes recent events concerning the assessment and regulation of formaldehyde, and evaluates the scientific data pertaining to the carcinogenicity of this substance in the context of established cancer policies and guidelines. The conclusion is that recent decisions by several federal agencies to defer action to limit human exposure to formaldehyde may be a "test case" for a new, less protective policy concerning the regulation of carcinogenic substances in general.

Formaldehyde↗
PubMed1981

Carcinogenicity of airborne fine particulate benzo(a)pyrene: an appraisal of the evidence and the need for control.

Benzo(a)pyrene(BaP) originating from fossil fuel and other organic combustion processes is largely adsorbed on fine particulate and hence is a widespread atmospheric pollutant. Available emissions and air quality data are based on the total weight of particulate matter without reference to size and give little information on trends and concentrations of fine particulate BaP. Greater reliance on coal, synfuels and diesel fuel for energy production and transportation will significantly increase ambient levels of BaP. Because of the particulate size, BaP is substantially deposited in the lower lung and readily eluted into surrounding tissue. After elution in the lung, BaP is metabolically activated to its electrophilic, carcinogenic from by a complex enzyme system whose activity is increased by prior exposure to air pollutants, cigarette smoke and certain drugs. The resultant diol epoxide metabolite has been shown to bind covalently with the DNA of the lung. In experimental animals, BaP is a potent initiating carcinogen whose action is enhanced by sulfur dioxide, promoting agents and carrier fine particles. The effect of small, divided doses of BaP has been shown to be greater than that of a single high dose; no threshold has been established. Epidemiological studies show that mixtures containing BaP (such as urban air, industrial emissions and cigarette smoke) are carcinogenic and may interact synergistically. Occupational studies indicate that the action of BaP-containing mixtures is enhanced in the presence of SO2. However, quantitative risk assessment for BaP is precluded by problems in extrapolating to the general population from small-scale animal studies; uncertainties in findings of epidemiology; and imprecise exposure data. Existing stationary and mobile controls preferentially remove coarse particulate matter and are inefficient collectors of the particulate BaP. In the current absence of health and environmental standards for BaP, there is little incentive to control BaP emissions. BaP meets the criteria for regulation under the Clean Air Act; however, no such BaP standards have yet been proposed.

Air Pollutants↗
PubMedDate not supplied

Preliminary studies on the effect of moderate physical activity on blood levels of glutathione.

Molecular epidemiological approaches are being used to study how physical activity may protect against cancer. Prior epidemiological data suggest that physical activity protects against lung cancer; however, interpretation of these data is complicated by potential confounding by smoking. Glutathione (GSH) detoxifies cigarette smoke carcinogens and the paper tests whether physical activity levels are associated with blood GSH levels. Study subjects were enrolled in a chemoprevention trial testing whether antioxidant micronutrient supplementation reduces genetic damage from cigarette smoking. Physical activity data were collected by questionnaire from 178 subjects at 12 months of follow-up in the trial. Total GSH (tGSH), which is the sum of free and protein-bound GSH and glutathione disulfide levels, was measured using the 5,5'-dithiobis-(2-nitrobenzenoic acid) colormetric assay with red blood cell samples collected at the 12-month time point. In multivariate linear regression analyses that controlled for gender and cigarettes smoked per day, tGSH was positively associated with hours per week of moderate intensity activity (beta=0.005, p=0.02). Hours per week of vigorous intensity activity were unassociated with tGSH and the effect of moderate activity remained after control for vigorous activity. The results are consistent with prior research showing differential effects of moderate and vigorous activity and suggest a mechanism through which physical activity may influence lung cancer risk.

Adult↗
PubMedDate not supplied

Biomarkers and molecular epidemiology of occupationally related cancer.

Effective prevention of cancer requires sensitive early warning systems to identify groups, and ultimately individuals, who are at high risk of developing cancer and to accurately estimate the magnitude of their risk. Incorporated with molecular epidemiologic studies, biologic markers have the potential to provide quantitative human data on the biologically effective dose of carcinogens, resultant molecular effects, and genetic/acquired factors that modulate these effects. Clearly, this information is directly relevant to risk identification and to risk quantification.

Biomarkers, Tumor↗
PubMedDate not supplied

[Evaluation of the relative potency of carcinogens: a critique of the HERP index].

In 1987 researchers from Berkeley (CA), proposed an index (HERP) for ranking human carcinogens. The index was derived from human exposure data and rodent carcinogen potency. They concluded that the risks for the US population from man-made industrial carcinogens are trivial compared with the risks from naturally occurring carcinogens in the diet. Analysis of the assumptions and data upon which the HERPs were based revealed major limitations and we concluded that such a simplified approach is inappropriate given the underlying uncertainties. However, when we made a comparison consistently based on estimates of average daily exposure to common carcinogens, the HERP scores of man-made pollutants were comparable to those of naturally occurring carcinogens.

Animals↗