Cancer Risk Assessment Methods in Occupational Epidemiology (Past Initiative)

Investigators are conducting research to develop or improve methods of surveillance, exposure measurements, and risk assessment that may be applicable in epidemiologic studies of cancer.

The projects are funded from proposals received in response to two Requests for Applications (RFAs March 1999, April 1999), co-sponsored by NCI, to stimulate methodologic research in occupational epidemiology, and to implement the National Occupational Research Agenda (NORA).

The Epidemiology and Genetics Research Program (EGRP) is supporting five research projects, and a fifth project is being co-funded with the National Institute of Environmental Health Sciences (NIEHS) (Keating).

Funding is for three years, beginning in September 1999, except for the co-funded project for which funding began in April 2000.

Distributed Occupational Knowledge System
Philip Harber, M.D.
University of California at Los Angeles School of Medicine
Department of Occupational and Environmental Medicine
Los Angeles, Calif.

Occupational health receives too little attention in primary care settings. In addition, public health surveillance acquires and utilizes too little of the information available in clinical settings. Obtaining an appropriate occupational history requires both time and expert knowledge about occupational medicine, both of which are inadequate in most primary care settings.

The Distributed Occupational Knowledge System (DOKS) addresses these problems by developing a computer assisted system, which may be directly incorporated in routine primary health care delivery. It obtains a computer-assisted occupational history and makes case-specific recommendations for preventive interventions. It will also systematically collect clinical information for public health analysis.

The system is being implemented in 3 types of ambulatory health care settings – county hospital-based, health maintenance organization, and clinic group. Initially, interviews will be in person, then by phone, and later by computer. Recommendations will be provided to patients and clinical care providers. Evaluation includes historical and concurrent controls and is based on exit and 3-month interviews and record review.

The process will also yield valuable surveillance data, including on population segments that are often missed by other methods, and describing functional impact of work, rather than just occupationally caused disease.

Improved Exposure Assessment for Organophosphate Pesticides
Garrett Keating, Ph.D.
University of California
Lawrence Livermore National Laboratory
Livermore, Calif.

This study will improve exposure assessment of pesticides by developing a methodology for measuring acetylcholinesterase (AChE) inhibition that includes determinations of free and total enzyme in the same blood sample.

The researchers will develop a methodology for preparing whole blood samples so that these measurements can be made sequentially using currently available methods for measuring cholinesterase activity that are used in clinical monitoring of pesticide exposure. They will calibrate colorimetric measurements of these AChE activities with specific binding of a radiolabeled probe to AChE in blood samples partially inhibited by an organophosphate (OP) pesticide.

Once analyzed by standard AChE assays, the samples will be processed to reactivate the OP-inhibited AChE followed by determination of this reactivated fraction through binding of the AChE-specific probe and colorimetric assay. This parallel AChE measurement approach is intended to validate the sequential colorimetric determinations so that the methodology can be performed without the radioactive assay.

This capability will improve exposure assessment of pesticides in several ways:

• knowledge of the total AChE activity in a blood sample will permit a more accurate estimate of the level of inhibition by utilizing individual-specific information,
• measurement of AChE activity is considered to be a more relevant endpoint for the neurological effects of pesticides than other cholinesterase activities, and
• the ratio of inhibited-to-total AChE will provide an internal standard to normalize the different AChE assays currently used to monitor pesticide exposure.

Multi-state Migrant Farmworker Surveillance Study
John May, M.D.
Northeast Center for Agricultural Occupational Health
Cooperstown, N.Y.

The Multi-State Migrant Farmworker Surveillance Study is investigating a new occupational injury and illness surveillance system, developed by the Northeast Center for Agricultural Occupational Health, and successfully piloted in New York and Pennsylvania. The new surveillance system uses the existing network of federally funded migrant health centers to track medical visits for work-related health problems, and collect anonymous medical chart data.

Occupational injury and illness rates obtained from the new surveillance system will be compared to those based on data on the same population from Worker's Compensation claims. In addition, the collected data will be used to identify leading occupational injury and illness types by region and work type, assess the importance of pesticides as a threat to farmworker occupational safety in the Northeast, and determine the consistency of occupational injury and illness patterns for leading commodities throughout the region.

This study has two broad objectives:

• increase the understanding of farmworker occupational injury and illness in the Northeast, and
• improve researchers' ability to collect migrant and seasonal farmworker injury and illness data throughout the country.

Cytogenetic Models for Assessing Low-dose Radiation Risk
Rainer Sachs, Ph.D.
University of California at Berkeley
Department of Mathematics
Berkeley, Calif.

Science-based assessments of environmental or occupational cancer risks from sparsely ionizing radiation estimate effects on large populations from doses that are very small compared to typical experimental doses and small compared even to epidemiologically tractable doses. A priority is developing credible dose-response relationships, both in an intermediate-dose range (up to 2 Gy or more) where epidemiology is feasible and in the most relevant, low-dose range (<0.1 Gy).

The pertinent initial damage, such as DNA double strand breaks, is almost certainly produced linearly with dose, so the main issue is cellular processing of initial damage via molecular repair/misrepair pathways, which can result in more complex endpoints such as chromosome aberrations and, ultimately, cancer. Exchange-type chromosome aberrations, produced during the GO/G1 cell cycle phase and scored at the next metaphase, are complex endpoints, characteristic of ionizing radiation damage and highly relevant to carcinogenesis risk estimation.

The goal is to use in vitro experiments on human cells and quantitative, mechanistic modeling to find realistic dose-response relations for such aberrations in a dose range from 0.08-2 Gy, as a practical surrogate for studying carcinogenesis in vivo at low doses. Biophysical and Monte Carlo computer analysis, comparing the best currently available models of molecular aberration formation pathways to data, is emphasized as a relatively inexpensive approach. The researchers have assembled a team of modelers and experimental radiobiologists from the University of California at Berkeley, Columbia University, and Harvard University for the research.

Exchange-type chromosome aberrations will be measured with state-of-the-art fluorescent in situ hybridization techniques after gamma-irradiation of human lymphocytes. Modeling will use extensions of sophisticated chromosome aberration simulator (CAS) computer software previously written and successfully applied by members of the research team.

The main novelties of the project are:

• close integration of mechanistic computer modeling with low-dose experiments, using repeated low-dose fractions to enhance response above background, including inversions and complex aberrations among the aberrations measured for risk-estimation purposes; and
• explicit consideration of the recombinational-repair aberration formation model.

The research project will help firm up risk estimates and make them more credible by studying quantitatively molecular mechanisms relevant to low doses and low dose-rates.

Development and Validation of A Mail Survey of Chemical Exposures
David Valiante, M.S.
New Jersey Department of Health
Occupational Health Service
Trenton, N.J.

This project is a 3-year hazard surveillance study with objectives to:

• develop and validate a prototype mailed, employer survey to assess the potential for worker chemical exposure and the controls in place to prevent exposure, and
• develop a method to score the surveys and rank facilities for priority for preventive activities.

Design Phase: Three draft versions of the Chemical Survey are mailed to groups of 40, 50, and 120 facilities that are asked to voluntarily complete the survey and discuss its clarity and ease of completion during a follow-up telephone interview with health department researchers. Survey responses and interview data are reviewed and the survey is revised accordingly.

Validation Phase: Following completion of the design phase, the final version of the survey is mailed to 1600 facilities in eight rounds of 200 facilities each. Facilities are asked to voluntarily complete the survey. Response accuracy is analyzed by conducting onsite visits with a random sample of respondents. Facilities are contacted by phone and a health department researcher visits those choosing to participate in the validation. The procedures and documents used to complete the survey are reviewed and employees observed. Job activities and related machinery, equipment, tools, and control measures are evaluated. Health department findings are compared to the information supplied by the employer. There are no repercussions for inaccuracies on the survey.

Ranking Phase: Surveys are scored and facilities are ranked by their priority for interventions, for example, education, consultation, regulation, and medical screening. There are separate ranked lists of facilities for each chemical and for different types of interventions. Ranking is based on analysis of key questions such as amount of chemical handled, patterns of handling, number of workers handling, worker job titles and duties, engineering controls in place, and personal protective equipment in use.

Chemicals Selected: The final survey requests information about specific chemical carcinogens that are in common use and, except for silica, for which there are comprehensive federal regulations. They are cadmium, benzene, crystalline silica, ethylene oxide (IARC category 1), formaldehyde (IARC category 2A), and lead and methylene chloride (IARC category 2B).

Types of Industry Selected: Industry groups are chosen based on research and expert industrial hygiene knowledge of where the selected chemicals are likely to be handled. Researchers use 4- and 8-digit Standard Industrial Classification (SIC) codes for selection from a Dun and Bradstreet employer database. The use of 8-digit codes allows for greater specificity in choosing types of industry.