Hyperprolactinaemia as an adverse effect in regulatory and clinical toxicology: role in breast and prostate cancer.

Historically, hyperprolactinaemia has been considered of low toxicological relevance when detected in toxicity studies, and even mammary carcinogenesis induced in the rat by prolactin excess has been considered of no relevance to humans. However, recent findings from human epidemiology and molecular biology suggests that prolactin is a risk factor for human breast cancer, and probably prostate cancer. Therefore, this new evidence should be considered in the various decisions to develop and license a new drug or chemical if the compound causes hyperprolactinaemia. This emerging evidence suggests that prolactin can also be produced locally from human breast cancer cells, and that, regardless of source (ie, pituitary or autocrine/paracrine production from cancer cells), prolactin is mitogenic, stimulates proliferation and suppresses apoptosis in breast and prostate cancer cells. This review outlines the evidence that hyperprolactinaemia should be considered a toxicological adverse effect and concludes that prolactin-induced rodent mammary carcinogenesis is relevant to humans and is not species-specific. The effects of prolactin on the prostate gland are also discussed; hyperprolactinaemia may be an additional risk factor for prostate cancer and this also requires consideration in toxicological risk assessments. The implications of increased prolactin secretion as an adverse effect for regulatory toxicology of drugs and chemicals, and in high risk patients receiving therapeutic drugs with hyperprolactinaemic side effects, is discussed. Alteration of prolactin level is also a novel mechanism that requires consideration in endocrine disruption research, since both endogenous oestrogens and also xenoestrogens stimulate prolactin secretion or affect prolactin receptors.

The impact of consuming iron from non-food sources on iron status in developing countries.

OBJECTIVE: : To determine the impact of contaminant iron and geophagy on iron intake and status of persons living in developing countries. DESIGN: : Literature for review was identified by searching Medline and Agricola, from appropriate other texts and from three reports from the Opportunities for Micronutrient Interventions (OMNI) Project of USAID. SETTING: : The dietary intake of iron by people living in developing countries is generally high but iron deficiency remains prevalent. This apparent paradox is because the iron being consumed is predominantly in the non-haem form, which is poorly absorbed. Some of this non-haem iron is from contamination of food with iron from soil, dust and water; iron leaching into food during storage and cooking; contamination during food processing such as milling; and the practice of geophagy. RESULTS: : Although the contribution of contaminant iron to overall iron intake is well documented, its absorption and thus its impact on iron status is not. To be available for absorption, contaminant iron must join the common non-haem pool, i.e. be exchangeable. The absorption of exchangeable contaminant iron is subject to the same interactions with other constituents in the diet as the non-haem iron that is intrinsic to food. The limited available evidence suggests wide variation in exchangeability. In situations where a significant fraction of the contaminating iron joins the pool, the impact on iron status could be substantial. Without a simple method for predicting exchangeability, the impact of contaminant iron on iron status in any particular situation is uncertain. CONCLUSIONS: : Interventions known to increase the absorption of iron intrinsic to foods will also increase absorption of any contaminant iron that has joined the common pool. Any positive effect of geophagy resulting from an increased intake of iron is highly unlikely, due to inhibiting constituents contained in soils and clays. The efficacy of approaches designed to increase the intake of contaminant iron remains encouraging but uncertain. An approach using multiple interventions will continue to be essential to reduce iron deficiency anaemia.

The dietary intake of chemical residues in Brisbane adults.

The purpose of this work was to integrate existing chemical residue and food consumption data for individuals to improve estimates of the dietary intake of chemical residues in the population of Brisbane. Previous estimates of intakes from the Australian Market Basket Survey (AMBS) have been based on energy-adjusted 'hypothetical national diets' and so allow no assessment of variation in intakes between individuals or groups. Data on concentration of fenitrothion, chlorpyrifos-methyl, pirimiphos-methyl, heptachlor and dieldrin in selected foods were taken from reports of the AMBS. Food consumption data were based upon the National Dietary Survey of Adults (NDSA) 1983; the same data from which the hypothetical diets are derived. The distribution of estimated 24-hour intakes was adjusted to represent usual intakes. Mean intakes of all residues were about one third those reported previously. None of the observed diets contained levels of residues that were greater than the Acceptable Daily Intakes. These findings support reassurances to the public that residues of agricultural chemicals monitored in the AMBS do not pose a health risk.

The development and evaluation of lighten up, an Australian community-based weight management program.

UNLABELLED: Programs of widely ranging size were conducted successfully in seven localities and thus the program was considered an operational success. The reductions in weight, blood pressure, and waist and hip measurements observed at the 3-month follow-up compared well with reports of other community-based programs. Almost all participants evaluated the program highly and reported positive changes in behaviors related to food and exercise. Qualitative data indicate that the coordinators developed a sense of ownership of the program--which will be vital to its sustainability. Rapport between coordinators and participants was more easily established in smaller programs than in larger ones and was an important underlying determinant of retention rates. SIGNIFICANCE: The Lighten Up program integrates environmental and individual strategies to facilitate changes towards a positive, lifestyle approach to long-term weight management. The program aims to establish sustainable social support networks with effective links to health services. This study has demonstrated that, with appropriate training and resources, existing public sector, primary health care personnel with no previous experience in health promotion can implement the program successfully in several communities concurrently. In the Australian context, this program can play an important role as one strategy in a range of interventions required to address the issue of obesity. The stepped-care model described by Brownell proposes that program options of varying intensity, and thus cost, be available to meet the variety of needs of overweight people who wish to lose weight. The Lighten Up program was close to the midpoint of that range in that it combined population strategies with one-on-one contact with health care personnel. LIMITATIONS: Participants in the study were self-selected people who had acted quickly to enroll in the program, and it is therefore likely that the sample was overrepresented with early adopters who may have been more successful than others would have been. We cannot tell from this developmental study whether or not the program will appeal to population groups known to be at high risk for obesity. This is an important question that needs to be addressed in future research. No control group was included in the design and thus we cannot be sure the benefits experienced by the participants resulted from the program. However, process evaluation data indicate that nothing that might explain the findings, other than the program, occurred in the communities during the time of the study. Further important issues to be evaluated include: the long-term maintenance of weight loss; whether or not the program will reach targeted populations, particularly groups of low socioeconomic status; and the extent to which the public health staff will maintain enthusiasm for the training and the programs.

Validity and reproducibility of a self-administered food frequency questionnaire in older people.

This study assesses the validity and reproducibility of a 145-item self-administered food frequency questionnaire (FFQ) in a representative older population aged 63 to 80. Semi-quantitative FFQs were completed by 89% of 3,654 residents attending a community-based eye study in Sydney, Australia. The FFQ's validity was assessed against three, four-day weighed food records (WFRs) completed four months apart by 79 people. A further 152 subjects completed a repeat FFQ about a year after the baseline FFQ, of whom 131 completed a second repeat FFQ about six weeks later. Both short and long-term reproducibility of the FFQ were assessed using data from these subjects. Comparison of the FFQ with the average of the three, four-day weighed food records resulted in energy-adjusted Spearman correlations above 0.5 for most of the nutrients. The proportion of subjects correctly classified to within one quintile category for each nutrient intake ranged from 57% for zinc to 82% for vitamin C. with most nutrients correctly classified within one quintile for about 70% of subjects. Quadratic weighted kappas were reasonable, between 0.3 and 0.5 for most nutrients. The FFQ was highly reproducible in the short term, with correlations for most nutrients about 0.70 to 0.80 and acceptably reproducible in the longer term, with correlations mostly 0.60 to 0.70. The results verify that it is possible to use relatively simple, but comprehensive, self-administered FFQs to study nutrient exposures in large-scale epidemiological studies of the elderly and to expect reasonably high FFQ response rates.

Comparison of self-report of reduced fat and salt foods with sales and supply data.

OBJECTIVE: Examine the validity of self-reported use of reduced fat and reduced salt foods. DESIGN: Compare data collected in a food frequency questionnaire with supermarket sales data and food supply data. SETTING: Rural Australia. SUBJECTS: Four hundred and fifty-three respondents from an original sample of 1616 randomly-selected residents. INTERVENTIONS: Community health campaign to reduce cardiovascular disease. RESULTS: Reported use of reduced fat and reduced salt foods was greater than store sales and milk deliveries of these products. CONCLUSIONS: External data did not support the validity of self-reported use of these products.

Milk consumption, galactose metabolism and ovarian cancer (Australia).

OBJECTIVES: It has been suggested that increased exposure to galactose, due to high consumption of dairy foods or reduced galactose metabolism, is associated with the development of ovarian cancer. We have investigated this in a large case-control study conducted in three Australian states between 1990 and 1993. METHODS: Approximately 800 histologically-confirmed cases, 800 community controls and 300 controls recruited through breast-screening clinics completed dietary questionnaires. Approximately 100 cases and all breast-screening controls also provided a blood sample for analysis of galactose-1-phosphate-uridyltransferase (GALT). RESULTS: Ovarian cancer risk was positively associated with increasing consumption of whole milk and other full-fat dairy foods, but was not associated with consumption of low-fat dairy foods and was inversely related to consumption of skimmed milk. There was no association between ovarian cancer and GALT except among women with abnormally low GALT who had a non-significant 2.5-fold increased risk of ovarian cancer. CONCLUSIONS: These data do not support the hypothesis that galactose plays a major role in the development of ovarian cancer and suggest that reported associations between milk consumption and ovarian cancer are due to the fat content of milk and not to lactose or galactose. An increased risk of ovarian cancer in women with abnormally low levels of GALT cannot, however, be ruled out.

The food-service industry, dietary guidelines and change.

The influence of the food-service industry on compliance with the Australian dietary guidelines was investigated through three separate methods of data collection and analysis: a telephone survey of 1683 randomly selected Brisbane residents; telephone interviews with 69 food-service-industry operators and 10 face-to-face interviews with key stakeholders in industry and government. Nearly 40 per cent of respondents had consumed foods prepared by the food-service industry at least once on the day before the interview, mainly from restaurants, cafes and takeaway shops, in the form of fast-food or snacks. Consumption of these foods declined with age. Those consuming foods prepared by the food-service industry ate significantly less fruit, vegetables and dairy food and were therefore less likely to comply with the dietary guidelines. Outcomes from interviews with operators in the food-service industry show that food choices offered to consumers were the result of a dynamic interaction between consumer demand and operators' own tastes and perceptions of food quality. Key informant interviews show that public health nutrition programs will have limited effect without supportive environmental changes in the food-service industry supply. An effective means of increasing the likelihood of compliance with the Australian dietary guidelines will be to encourage food suppliers in ways that address their core business concerns simultaneously with the goals of health professionals.

Food insufficiency in Queensland.

To investigate the prevalence of food insufficiency and factors associated with it, two questions assessing household and individual food insufficiency were included in 13 regional health surveys conducted in Queensland in 1993. The surveys used computer-assisted telephone interviewing methodology. Of the 10,451 people interviewed, 9.7 per cent and 6.4 per cent reported household and individual food insufficiency, respectively, and 11.3 per cent reported at least one type. Prevalence was significantly higher in women than men and in urban than rural residents, and decreased monotonically with increasing age from 16.6 per cent in 18- to 30-year-olds to 1.7 per cent in over-70-year-olds. Higher prevalence also was associated with lower income, unemployment, single or separated, divorced or widowed status versus married (or de facto), one-adult households, and shared accommodation. Lower prevalence was associated with more education in those aged 50 and under but not in those over 50 years. Using logistic regression to control simultaneously for important sociodemographic factors, we found that risk of food insufficiency was most highly associated with age and income (threefold risk), unemployment and shared accommodation (twofold risk) and one-adult households, and being single versus separated, widowed or divorced (one-and-a-half-fold risk). Some differences in risks existed between men and women and between rural and urban residents, although none excluded the role of chance. Association of the items with lower reported fruit, vegetable and meat intake, poorer health status, and greater underweight supports their validity.

Involvement of deprivation and environmental lead in neural tube defects: a matched case-control study.

OBJECTIVE: To analyse the prevalence of neural tube defects in small geographical areas and seek to explain any spatial variations with reference to environmental lead and deprivation. SETTING: The Fylde of Lancashire in the north west of England. DESIGN: Cases were ascertained as part of a prospective survey of major congenital malformations in babies born in the Fylde to residents there between 1957 and 1981. A matched case-control analysis used infants with cardiovascular system, alimentary tract, and urinary system malformations as controls. Conditional logistic regression was used to assess the effects of more than 10 micrograms/l lead in drinking water and the Townsend deprivation score. RESULTS: The prevalence of neural tube defects in 1957-73 was higher in Blackpool, Fleetwood, and North Fylde, whereas the three control groups showed no significant spatial variation. In 1957-81 mothers living in electoral wards with either a higher proportion of houses with more than 10 micrograms/l lead in the water or a higher deprivation score had a greater risk of having a baby with a neural tube defect. For spina bifida and cranium bifidum alone, this was also true. For anencephaly, deprivation was less important although the effect of lead was still seen. In some neural tube defects, lead may act independently of other possible factors associated with deprivation. It seemed unlikely that lead levels changed significantly during the survey. The percentage of houses with 10 micrograms/l or more of lead in the water in 1984-5 was similar to that found in Great Britain 10 years previously. CONCLUSION: There is evidence to suggest that lead is one cause of neural tube defects, especially anencephaly. This could link the known preventive actions of hard water and folic acid. Calcium is a toxicological antagonist of lead. One cause of a deficiency of folic acid is impaired absorption secondary to zinc deficiency, which may be produced or exacerbated by lead.

Development of a dietary supplement database.

Data describing the composition of dietary supplements are not readily available to the public health community. As a result, intake from dietary supplements is generally not considered in most dietary surveys and, hence, little is known about the significance of supplement intake in relation to total diet or disease risk. To enable a more comprehensive analysis of dietary data, a database of the composition of various dietary supplements has been compiled. Active ingredients of all dietary supplements sold in Australia are included in the Australian Register of Therapeutic Goods (ARTG), maintained by the Therapeutic Goods Administration. Products included in the database were restricted to those vitamin, mineral and other supplements identified in dietary data collected from studies conducted in southeast Queensland and New South Wales (850 supplements). Conversion factors from ingredients compounds to active elements were compiled from standard sources. No account has been made for bioavailability, consistent with current practice for food composition databases. The database can be queried by ARTG identification number, brand, product title, or a variety of other fields. Expected future developments include development of standard formulations for use when supplements are incompletely specified, and expansion of products included for more widespread use.

Glucocorticoid amelioration of nephrotoxicity: a study of cephaloridine-methylprednisolone interaction in the rat.

Groups of ten male rats were treated with a high challenge dose of cephaloridine (CPH, 3750 mg kg-1), with methylprednisolone (MP, 100 mg kg-1) or with cephaloridine and methylprednisolone (CPH + MP) by single subcutaneous injection. A control group received the injection vehicles only. Urine was collected from all animals daily over 18-h collection periods, up to 96 h after treatment. Blood was collected at 24, 48, 72 and 96 h after treatment. At necropsy, kidneys were weighed, processed and examined histopathologically. Results show that methylprednisolone significantly ameliorated the nephrotoxicity of the challenge dose of cephaloridine. CPH-only treated rats had severe toxic nephrosis characterised by acute tubular necrosis, and elevated blood urea and creatinine. By contrast, the majority of CPH + MP treated rats had only a slight or moderate toxic nephrosis, and had lower blood urea and creatinine levels compared with rats treated with CPH only, indicating preservation of kidney function. Interestingly, rats treated with CPH + MP had higher urinary enzymes (alkaline phosphatase, lactate dehydrogenase, gamma glutamyltransferase and N-acetyl-beta-glucosaminidase) as well as protein and glucose, compared with rats treated with CPH only. This is taken to indicate that rats treated with CPH only had such marked kidney damage and necrosis that the population of cells able to produce these marker enzymes was significantly and rapidly depleted, but the protection afforded by methylprednisolone allowed CPH + MP treated rats to sustain urinary enzyme output. Effects on urinary glucose and other parameters such as body weight and kidney weight demonstrate interactions between glucocorticoid pharmacology and cephaloridine nephrotoxicity.(ABSTRACT TRUNCATED AT 250 WORDS)

Down's syndrome: prevalence and ionising radiation in an area of north west England 1957-91.

OBJECTIVE: To analyse the prevalence of Down's syndrome in a specific, geographical area and seek to explain variations with particular reference to ionising radiation. DESIGN: Cases were ascertained by one paediatrician as part of a prospective survey of major congenital malformations in children born to residents of an area of Lancashire between 1957 and 1991. Temporal changes in prevalence rates were detected by a grid search technique using Poisson log linear models. These models were also used to determine the association between prevalence and ionising radiation from atomic fall out. SETTING: The Fylde district of Lancashire in the north west of England. PATIENTS: There were 167 cases, including five stillbirths and eight terminations, among 124,015 total births in a population which increased from about 250,000 to over 300,000 during the study period. MAIN RESULTS: There was significant increase in the prevalence of all cases conceived in 1963 and 1964, and a lesser peak in 1958 which did not quite reach statistical significance. There was no evidence that the increased prevalence in 1963-64 was a result of changes in the maternal age distribution in the population. Babies of mothers aged 35 years and over accounted for more of the variation, especially in 1958 when their increase was significant. There was a highly significant association between prevalence and radiation from fallout produced by atmospheric testing of atomic weapons. The 1963-64 peak coincided with the maximum estimated radiation dose. The lesser peak in 1958 also coincided with increased exposure to radiation from fallout, possibly enhanced by ground deposits after a fire at the Windscale reactor in October 1957. CONCLUSION: This study provides further support for low dose ionising radiation as one aetiological factor in Down's syndrome.

Glucocorticosteroid interactions with natural toxins: a mini review.

A growing area of research in pharmacology and toxicology is concerned with the role of adrenal glucocorticosteroids (predominantly corticosterone in rats and mice, and cortisol in humans) in modulating toxicological responses. These steroids are secreted from the adrenal cortex, and in laboratory rodents secretion occurs particularly in response to stressful environmental change or noxious challenge, which can include a toxic insult. Glucocorticoids have profound biochemical effects in diverse tissues (e.g., inhibition of DNA and RNA synthesis; effects on carbohydrate metabolism, protein catabolism, and immunosuppression, and anti-inflammatory effects). Given this range of pharmacological actions of glucocorticoids, effects on the response and tolerance to a toxic insult can be hypothesised. Indeed, it is now becoming clear that the toxicological response to a toxin can be modulated by pretreatment with, or coadministration of, natural glucocorticosteroids or their synthetic analogues. As achieving the maximum tolerated dose (MTD) in an experimental animal, whether via a natural toxin or a synthetic chemical, can be stressful, the implications of these findings are far reaching. This review is intended to illustrate the principle that the toxicological responses to natural toxins (e.g., kainic acid, aflatoxin B1, trichothecenes) can be modulated by corticosterone and other natural and synthetic glucocorticosteroids. Particular emphasis is given to neurotoxicity and hepatotoxicity in laboratory rodent models, but nephrotoxicity and cardiotoxicity, of which there are fewer studies, are also covered. Glucocorticoids can both enhance toxicity or protect against toxicity, and the direction of the effect depends on the target organ, the particular steroid, the properties of the toxin, and the temporal relationship of the coadministration regime.