Gender Differences in Cancer Incidence R Benigni and A Giuliani, Istituto Superiore di Sanita `, Rome, Italy & 2011 Elsevier B.V. All rights reserved. Abbreviations BRCA1 breast cancer 1 CPDB Carcinogenic Potency Database EPA Environmental Protection Agency NTP National Toxicology Program PC principal component PCA principal component analysis SEER Surveillance, Epidemiology and End Results TD tumor dose Introduction Despite the considerable efforts and funds that have characterized the research on cancer in the past decades, cancer is still not defeated and remains largely a lethal disease. Cancer is the second leading cause of death in Western countries, just after circulatory diseases. At odds with an image diffused by most media that focus largely on genes and genetic research, the causes of cancer are predominantly environmental in nature (this includes lifestyle, diet, and work). Different types of evidence converge toward an estimated 80% environ- mental component of cancer. In fact, classical studies on the geographic distribution of tumors, and on the changes that take place in tumor profiles and incidence in migrant populations, show that the migrants acquire the same patterns shared by the population in situ in one or two generations’ time. Along the same line of evidence, epi- demiologic studies have shown that the concordance in cancer incidence in monozygotic twins is substantially similar to that in dizygotic twins: this suggests that in- herited genetic factors make a minor contribution to the susceptibility to most types of neoplasms. This evidence is supported by the attempts to measure the correlation between genetic patterns (expressed either as genetic fingerprint distance, or as distribution of ABO blood groups) and the cancer incidence directly in populations: it appears that the correlation between genetic settings and cancer incidence is in the range 10–20%. Having ruled out a major role of pure genetically heritable fac- tors in cancer incidence that allow to consider cancer as neither a ‘genetic disease’ nor a pathology in which the presence of specific genes plays a considerable role as predisposition modifiers (with some notable ex- ceptions such as breast cancer 1 (BRCA1) gene for breast cancer, in any case these exceptions have a negligible impact on global tumor burden), the effect of other possible major modifiers of cancer susceptibility is of utmost importance. Gender – together with age and species – is the main feature that must be considered when studying any bio- logical aspect in mammalians and consequently a possible candidate to play a major role in cancer incidence profile. Depending on the level at which the investigation is performed, this factor acquires different determinations and exerts its influence through different routes. Whereas epidemiology has a central role in the study of cancer, since it provides the definitive evidence about a causal relationship between human cancers and environmental determinants (such as definite chemicals or exposures), the experimental investigations – when feasible – are an invaluable tool in all those cases in which the human exposure cannot be studied directly. This also includes situations in which the epidemiologic studies have no sufficient potency for discovering relationships hidden by confounding factors or very low and variable exposures. The main experimental tool used to study cancer is the 2-year rodent bioassay. The present article will consider the evidence first from animal studies and then from epidemiologic studies. The two lines of evidence provide complementary information. Gender Differences in Experimental Carcinogenesis in Rodents Because of its central role in the regulation of chemicals, the rodent bioassay has been under intense scrutiny and has been demonstrated to be a valid basis for human risk assessment. The classical protocol adopted today includes four experimental groups of animals: rat and mouse, male and female. The preferred number of animals in each group is 50. Concomitant control groups are included in the experimental design. The animals are treated for 2 years, at two or more doses of the chemical. The application of the rodent bioassay to individual chemicals or mixtures provides three main types of information: (1) yes/no responses in the different ex- perimental groups that concur to define the overall car- cinogenicity call of the chemical and (2) potency of the carcinogenic compounds. For each tumor type induced, a potency index can be calculated (e.g., TD 50 (tumor dose), which is the dose required to halve the probability of the 839