Anthony J. McMichael

Diet, acetylator phenotype, and risk of colorectal neoplasia

BACKGROUND Inherited or acquired differences in metabolic pathways that activate or inactivate dietary carcinogens may influence the risk of developing cancer. A polymorphism in N-acetyltransferase classified people into fast and slow acetylators. This enzyme catalyses the formation of mutagenic products from foodstuffs, especially cooked meat and fish. Some data suggest that fast acetylators are at higher risk of colorectal cancer. We have studied the adenoma and cancer risk in relation to meat intake and acetylator status. METHODS In a case-control study, we compared 110 patients with colorectal cancer, 89 patients with colorectal adenomatous polyps, and 110 controls. Acetylator status was assessed by the rate of acetylation of sulphamethazine given orally. FINDINGS The fast-acetylator phenotype was associated with odds ratios of 1.1 (95% Cl 0.6-2.1) and 1.8 (1.0-3.3) for adenoma and colorectal cancer, respectively. The highest risk occurred in the youngest tertile (< 64 years) of cases (2.5 [0.7-9.4] and 8.9 [2.6-30.4], respectively). There was no difference between the sexes. The risk of adenoma or cancer increased with increasing intake of meat in fast but not in slow acetylators: covariate-adjusted odds of disease over three levels of meat consumption were 2.1 (0.9-4.7) for adenoma, 1.7 (0.9-3.5) for cancer, and 1.9 (1.0-3.7) for all tumours. INTERPRETATION Our findings indicate that acetylator status modulates the risk of colorectal neoplasia associated with meat intake.

Dietary factors and survival from breast cancer

The association between self-reported intake of various dietary factors at diagnosis and survival from breast cancer was studied in a population-based cohort of breast cancer patients in Adelaide, South Australia. These patients had been recruited between 1982 and 1984 into a case-control study of diet and incident breast cancer. Of the 451 patients recruited originally, 412 were followed for a median interval of 5.5 years. There were decreases in the risk of death from breast cancer ranging from 25 to 40% at all levels of energy and protein intake above the baseline, whereas for fat intake there was a 40% increase in risk at the uppermost quintile level. There was also some reduction in risk at the upper levels of intake of beta-carotene and vitamin C. However, there were no dose-dependent variations in risk of death by level of intake for any of the dietary factors studied, and most of the variation in risk that was observed was relatively insubstantial.

Determinants of Blood Lead Concentrations to Age 5 Years in a Birth Cohort Study of Children Living in the Lead Smelting City of Port Pirie and Surrounding Areas

Sources of variation and some principal determinants of blood lead concentration (PbB) were investigated in a cohort of children, followed to age 5 y, who were born near a lead smelter in Port Pirie, South Australia. The childs age and place of residence were the two variables most strongly predictive of PbB. A sharp increase in PbB occurred between 6 and 15 mo of age and was followed by a peak concentration that occurred at approximately 2 y of age, after which PbB steadily and consistently declined. Irrespective of age, the PbBs in children who lived in Port Pirie were significantly higher than levels identified in children who resided outside the city. There was no significant difference in PbB between boys and girls. Elevated PbB at each specific age was associated mainly with increased lead concentrations in the topsoil of the local residential area, employment of the father in the lead industry, parental smoking, and behaviors likely to cause ingestion of dirt. Blood samples taken from children at certain ages and during the warmer months contained more lead than samples obtained during the cooler months. The effects of these determinants on PbB during early childhood were basically consistent in both single and multivariable analyses.

Sociodemographic factors modifying the effect of environmental lead on neuropsychological development in early childhood

A long-term prospective cohort study was conducted to examine the association between prenatal and postnatal exposure to environmental lead and childhood neuropsychological development. The possible interactive effects of blood lead and some covariates on early development were explored in this study. Our data suggest that gender of the child modifies the effect of lead on the neuropsychological development during early childhood. At the ages of 2 and 4 years, girls appear to be more sensitive than boys to the neuropsychological effects of lead. However, there is no significant modification of the effect of lead by some other covariates, such as parental smoking, socioeconomic status, home environment, birth weight, and the kind of infant feeding. Evidence of interactions between environmental lead exposure and other covariates in the causation of neuropsychological deficits in childhood underscores the desirability of considering both main effects and interactions in this area of research. Such effects, if confirmed, may have implications for public health intervention strategies.

Amalgam fillings, diagnostic dental X-rays and tumours of the brain and meninges

A population-based case-control study of incident brain tumours in adults in Adelaide, South Australia considered possible associations of exposures to amalgam fillings and diagnostic dental X-rays with subsequent development of glioma and meningioma. The study, conducted in 1987-1990, recorded data from 110 subjects with glioma, 60 with meningioma and 417 controls. Principal findings were unexplained decreased risks for glioma associated with both exposure to amalgam fillings (age- and sex adjusted relative risk = 0.47, 95% confidence interval: 0.25-0.91; P = 0.02) and to diagnostic dental X-rays (adjusted relative risk = 0.42; 95% confidence interval: 0.24-0.76; P = 0.004), and a possible increased risk for meningioma in males exposed to dental X-rays. The choice of the unexposed comparison group is important in determining if an increased risk is associated with panoramic or full-mouth X-rays in glioma.

Stable lead isotope profiles in smelter and general urban communities: a comparison of environmental and blood measures

High-precision lead isotope ratios and lead concentrations have been compared statistically and graphically in women of child-bearing age (n = 77) from two smelter communities and one general urban community to evaluate the relative contributions to blood lead of tissue lead stores and lead from the contemporaneous environment (soil, floor dust, indoor airborne dust, water, food). Blood lead (PbB) contents were generally low (e.g. <10 μg dL−1). Statistically significant isotopic differences in blood and environmental samples were observed between the three cities although isotopic differences in blood for individual subjects living in close proximity (∼200 m radius) was as large as the differences within a city. No single environmental measure dominated the biological isotope profile and in many cases the low levels of blood lead meant that their isotopic profiles could be easily perturbed by relatively small changes of environmental exposure. Apportioning of sources using lead isotopes is possibly not feasible, nor cost effective, when blood lead levels are <5 μg dL−1. Interpretations based on statistical analyses of city-wide data do not give the same conclusions as when the houses are considered individually. Aggregating data from multiple subjects in a study such as this obscures potentially useful information. Most of the measures employed in this study, and many other similar studies, are markers of only short-to-medium integration of lead exposure. Serial sampling of blood and longer sampling times, especially for household variables, should provide more meaningful information.

Risk factors for ulcerative reflux oesophagitis: a case-control study.

Abstract A case‐control study was undertaken to investigate the effects of smoking, alcohol consumption, use of non‐steroidal anti‐inflammatory and other analgesic medications and family and medical history on the risk of ulcerative reflux oesophagitis (URO). We recruited 191 cases with URO diagnosed at endoscopy, 162 hospital controls who had also undergone endoscopy and 140 community controls from the Adelaide metropolitan area. From these three groups of subjects, 134 case‐community control pairs, matched on age, sex and postcode of residence and 142 case‐hospital control pairs, matched on age, sex, hospital and endoscopist, were formed. Elevated non‐significant risks were found in those smoking at least 20 cigarettes per day relative to those who never smoked (relative risk = 1.9, 95% confidence interval: 0.9‐3.9 in case‐hospital control pairs; relative risk = 1.9, 95% confidence interval: 0.9‐3.7 in case‐community control pairs). There was no elevation in risk associated with the use of non‐steroidal anti‐inflammatory drugs, with alcohol consumption, factors related to medical and reproductive history, nor with family history except for paternal history of heartburn (relative risk = 2.5, 95% confidence interval: 1.2‐5.4 in case‐hospital control pairs; relative risk = 1.9, 95% confidence interval: 1.0‐4.0 in case‐community control pairs). With the possible exception of smoking, no other risk factors for ulcerative reflux oesophagitis related to lifestyle are apparent.

Some characteristics and correlates of blood lead in early childhood: preliminary results from the Port Pirie study

In 1979 the recruiting of pregnant women for a prospective study of pregnancy outcome and early childhood growth and development was commenced in the South Australian town of Port Pirie. The Port Pirie community has been exposed over many years to an accumulation of lead and other heavy metals, because of the operation of Australias largest lead smelter on the immediate periphery of the town. The basic aim of the study was to relate early childhood growth and development to cumulative lead exposure. Other specific aims included studying the relationship between childhood lead burden and various behavioral, dietary, socioeconomic, and environmental factors thought likely to influence lead exposure. This paper relates, in a simple cross-sectional manner, the observed blood lead concentrations at 6, 15, and 24 months to the supplementary information obtained by questionnaire and interview with the mother at the times the blood samples were taken. The relationship between blood lead concentration and free erythrocyte protoporphyrin (FeP) at each age is also examined. 12 references, 1 figure, 2 tables.

Diet and cancer: Value of different types of epidemiological studies

Diet and nutrition are increasingly recognized as likely to be major determinants of cancer, notably cancers of the gastrointestinal tract, breast, endometrium, ovary, and prostate. Dietary factors may collectively account for a greater proportion of all cancers that occur in contemporary Western society than does any other category of environmental exposure (1). With the development of knowledge of the protective properties of certain components of food, links with diet have been suggested for other cancer sites (2). The epidemiological evidence for the association of diet and cancer is, however, not uniformly convincing; also, the likely biological pathways are not always clear. In this paper, we comment on some current hypotheses in this area and examine the best epidemiological methods to test them.

Metabolic phenotypes and colorectal neoplasia

Abstract It now appears likely that the development of colonic adenomas and carcinomas involves a series of steps in which environmental or endogenous carcinogens induce or promote neoplasia through the accumulation of multiple, specific genetic mutations. Genetic predisposition to this process may take the form of inherited defects in control of cellular proliferation as in familial polyposis coli, or genetically determined polymorphism which affects enzyme activities relevant to the production or detoxication of carcinogens. Genetic effects may also influence levels of hormones and/or their target cell receptors which regulate the metabolic and proliferative activity of colonocytes. This review highlights data suggesting a role for polymorphism associated with xenobiotic acetylation, hydroxylation, and conjugation with glutathione in the metabolism of potential carcinogens, as well as for dehydroepiandrosterone in the metabolic control of cell proliferation. The study of genetically determined polymorphism in colorectal cancer may provide new insights into the epidemiology of cancer and result in new methods for the detection of higher risk groups.