Silica-induced new type of DNA damage; does antiandrogen carcinogens sensitize men for silica-induced cancer?

Research problem and specific questionsIn Sweden, quartz exposure is one of the biggest risk factors for work-related mortality. The EU´s (and Sweden´s) quartz exposure limit value (OEL) does not protect against lung cancer. Quartz is thus causing the highest death rates of all occupational carcinogens in the EU.

Based on a new type of DNA damage, we intend to provide a basis for a lowered OEL.

The study aims to 1) define the lowest exposure that causes DNA damage 2) correlate micronuclei in oral epithelium to occupational exposure 3) study the role of the androgen receptor in synergistic effects between quartz, occupational carcinogens and smoking 4) investigate whether older men and men with low testosterone levels are susceptible to quartz-induced DNA damage.Data and methodOur published and preliminary data show that quartz induce enzyme-DNA damage.

It is induced quickly, is very easy to detect and thus differs markedly from earlier described quartz-induced DNA damage.

The methods to demonstrate DNA damage include human oral and bronchial epithelium, human stem cells, human explanted bronchi and mice. The results will be related to human data from occupationally exposed people.

We will be collaborating with the SYNERGY study group at IARC on their novel quartz cancer data.Plan for project realizationUsing our models, the DNA damage threshold for quartz should be specified. The relevance of the models is tested against epidemiology and biomonitoring data.

Thus, gender differences and the role of the androgen receptor in DNA damage will be studied to shed light on demonstrated interactions with smoking and other work environment carcinogens e.g. chromium.

The biomonitoring model will be used to relate our doses to occupational exposure.Societal relevance and utilizationThis study will generate knowledge about threshold levels for quartz-induced mutations. Lack of knowledge in this area might have permitted the excessively high limit value.

We expect the project to provide data for a lowered OEL by affecting the EU´s risk assessment and risk management of quartz.

The study will lead to new knowledge about quartz´s low-dose carcinogenic ability and about how quartz interacts with other carcinogens. Quartz exposure is extensive, and our project will provide basis for better risk management and safer work environment.