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 effect of iron therapy on malarial infection in Papua New Guinean schoolchildren.

The effect of iron therapy on malarial infection was investigated in Papua New Guinea, where malaria is endemic. Prepubescent schoolchildren with hemoglobin levels of 8-12 g/dl were randomly assigned to receive either 200 mg ferrous sulfate or a placebo twice daily for 16 weeks. Iron status and malarial infection were assessed at baseline, after 6 and 16 weeks of therapy, and 8 weeks after therapy was discontinued. Iron status was significantly improved by the treatment. The treatment did not significantly affect parasite rate, parasite density, or levels of anti-malarial IgG. No changes in spleen size were observed in either group. Furthermore, there was no significant difference between the groups in reported episodes of suspected malaria during the therapy. These results suggest that, in malaria endemic areas, oral treatment for iron deficiency can be carried out in semi-immune or immune schoolchildren without adverse consequences.

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.

Seasonal prevalence of major congenital malformations in the Fylde of Lancashire 1957-1981.

The seasonal prevalence of major congenital malformations was studied in a prospective survey of 88,449 children born in the circumscribed Fylde of Lancashire to residents there over 25 years. Ascertainment was thought to be as complete as was practically possible because cases were recorded daily by one, and for 17 years the only, paediatrician and a very high rate of necropsies was maintained. The number of malformations were classified by month of maternal last menstrual period and seasonal variation was assessed by three statistical models. Neural tube defects showed a significant seasonal variation in month of last menstrual period but not in month of birth. From May 1956 to April 1968, when the prevalence of neural tube defects was high (5.5 per 1000 total births), conceptions were significantly more common in December to May. For anencephaly alone the figures were not significant, but spina bifida and cranium bifidum were more common in March to May. From May 1968 to April 1981, when the prevalence of neural tube defects fell below the national average, the significant variations disappeared. Seasonality for spina bifida and cranium bifidum was seen only in "singles" (cases with no other major lesion), but for anencephaly it was seen only in "multiples" (cases with other lesions). The three types of cardiac septal defect and persistent ductus each showed a higher prevalence of conceptions at some time during May to October. In contrast the commonest group of cyanotic cases showed no such pattern but with greater numbers in winter. There was evidence of a seasonal variation for bilateral renal agenesis and for vesicoureteric reflux as ascertained. Seasonal prevalence in an aetiological factor for certain malformations of the central nervous system, cardiac and urinary systems.

The incidence of anencephalus in the Fylde peninsula 1956-76 and changes in water hardness.

In an area which had a high incidence of anencephalus, 3.2 per 1000 births, there was a significant drop to 1.3 per 1000, below the national average of 1.7 to 1.8, among conceptions after 1967. In the northern part of the area this drop was greater in summer than winter conceptions, providing additional evidence of a different process underlying case occurrences in the north of the area from that in the south. In 1957-61 there were significantly more births of anencephalic babies in North Fylde than in South Fylde, but both areas were supplied with soft water. From 1962 to 1969 the water changed from soft to slightly hard. Soft water does not appear to be a primary aetiological factor in anencephalus, but hard water may mitigate the effect of other factors.

Congenital malformations in the Fylde region of Lancashire, England 1957-1973.

This paper uses data collected by a consultant paediatrician to examine variations in the prevalence of neural tube and cardiovascular malformations within the Fylde region of North West England. Results at the district scale indicate contrasts in the geographical distributions of the two classes of malformation and these are then further assessed via a case-control study which standardises for factors such as date of conception, age of mother and parity. The results of this study suggest that there were wards in Blackpool and Fleetwood with unusually high prevalences of neural tube defects. Further research is being undertaken to identify the causes of these concentrations.

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.

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.

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.

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.

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.

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.

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.

Corticosterone does not cause testicular toxicopathology in the rat: relevance to methylxanthines, ACTH and stress.

1. Methylxanthines, ACTH and stress are well known to produce testicular pathology (e.g. seminiferous tubule atrophy). Methylxanthines, ACTH and stress alter hormone secretion, particularly from the pituitary-adrenocortical system. Consequently, it has recently been suggested that there may be a causal relationship between changes in endogenous physiological adrenocortical secretions, particularly corticosterone, and testicular pathology. 2. This study tested the hypothesis that corticosterone mediates the testicular effects of both methylxanthine treatment and stress. Corticosterone was administered daily by subcutaneous injection to groups of 10 male rats at dose levels of 2 or 20 mg kg-1 in propylene glycol (1 ml kg-1) for 1 month (the shortest duration of methylxanthine or ACTH exposure known to produce testicular pathology). The highest dose of corticosterone resulted in plasma concentrations that closely matched values resulting from stress (200-700 ng ml-1) compared with controls (< 25 ng ml-1). 3. The highest dose of corticosterone caused reduced body weight gain, lower thymus, adrenal, seminal vesicle and prostate weights, but did not induce any testicular pathology. 4. That a high, but physiologically relevant, dose of corticosterone did not cause testicular pathology in this experiment excludes this steroid in the direct aetiology of methylxanthine, ACTH and stress-induced testicular pathology. Other steroids secreted from the adrenal, in combination with corticosterone, may be involved.

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)

Growth patterns of children in Lagaip, Enga Province.

A nutrition survey was conducted in 1979 in the Lagaip area of Enga Province. On examining 1,739 children under 5 years., it was found that the pattern of their growth was similar to that reported in other highland populations. The high proportion (37%) of the children classified as malnourished results from stunting, not wasting. Most of the children classified as wasted were less than 2 years old. Significant associations were found between reported morbidity and nutritional status when the latter was assessed by weight related indices.

PIP: A nutrition survey was conducted in 1979 in the Lagaip area of Enga Province to establish anthropometric baseline data for children under 5 years of age. Undernourished children are at a greater risk of morbidity and mortality and the numbers at risk and their location need to be known so that adequate preventive resources can be allocated. Data are reported on 1206 children who were selected from the population attending Maternal and Child Health clinics in the area using a stratified sampling procedure. Measurements of weight, length, mid-upper arm circumference, and triceps skin-fold were taken and compared against standards reported by Jelliffe. A morbidity questionnaire was also administered to the guardians of the children. Using the weight for age measurements, 37% of the study children are classified as malnourished. The most prevalent form of malnutrition is stunting (deficit in length for age). Only 3% of the sample are wasted (deficit in weight for length), with a majority, 81%, under 2 years old. The proportion of children neither wasted nor stunted falls steadily with age to 39% in the 5th year of life. Stunting, unlike wasting, is not amenable to nutritional intervention. Preventive programs to increase energy and protein intake should be aimed at children 4 to 15 months old, a critical age range when prevention is important.