Safe levels of cadmium intake to prevent renal toxicity in human subjects

The present review attempts to provide an update of the scientific knowledge on the renal toxicity which occurs in human subjects as a result of chronic ingestion of low-level dietary Cd. It highlights important features of Cd toxicology and sources of uncertainty in the assessment of health risk due to dietary Cd. It also discusses potential mechanisms for increased susceptibility to Cd toxicity in individuals with diabetes. Exposure assessment on the basis of Cd levels in foodstuffs reveals that vegetables and cereals are the main sources of dietary Cd, although Cd is also found in meat, albeit to a lesser extent. Cd accumulates particularly in the kidney and liver, and hence offal contains relatively high amounts. Fish contains only small quantities of Cd, while crustaceans and molluscs may accumulate larger amounts from the aquatic environment. Data on Cd accumulation in human kidney and liver obtained from autopsy studies are presented, along with results of epidemiological studies showing the relationship between renal tubular dysfunction and kidney Cd burden. These findings suggest that a kidney Cd level of 50 mug/g wet weight is a maximum tolerable level in order to avoid abnormal kidney function. This renal Cd burden corresponds to a urinary Cd excretion of 2 mug/d. Accordingly, safe daily levels of Cd intake should be kept below 30 mug per person. Individual variations in Cd absorption and sensitivity to toxicity predicts that a dietary Cd intake of 30 mug/d may result in a slight renal dysfunction in about 1% of the adult population. The previous guideline for a maximum recommended Cd intake of 1 mug/kg body weight per d is thus shown to be too high to ensure that renal dysfunction does not occur as a result of dietary Cd intake

An investigation of hookworm infection and reinfection following mass anthelmintic treatment in the South Indian fishing community of Vairavankuppam

Hookworm infections, as assessed by counting worms expelled following anthelmintic treatment and by egg output, were found to be of low prevalence and intensity in a South Indian fishing community. The initial overall prevalence of infection in the community was 43 %, and the average burden was estimated at 2.2 hookworms per person. The age profiles of prevalence and intensity differed between males and females, with the latter harbouring significantly higher levels of infection. Children of both sexes under 10 years of age rarely harboured hookworms. Treatment with pyrantel pamoate was estimated to be 91 % effective in clearing hookworm infections. Egg counts made on stools collected during an 11-month period of reinfection indicated that female patients became reinfected soon after treatment, while little hookworm egg excretion was observed in males during the observation period following treatment. Females acquired a significantly higher number of worms during the reinfection period compared with males, although the average burden in females reached only 28% of the initial, pre-treatment level. The hookworm population consisted of predominantly Necator americanus, and less than 10% of Ancylostoma duodenale. The parasites were highly aggregated within the host population with 10% of the community harbouring over 65% of the total hookworms. Low values of the negative binomial aggregation parameter, k, (indicating extreme over-dispersion) were recorded in groups stratified by age and sex. Highly significant positive correlations were observed between the initial (pre-treatment) and reinfection worm burdens of female (but not of male) patients. It is suggested that occupational practices related to walking through areas contaminated with hookworm larvae play an important role in generating the observed patterns of infection within this community.</p

The importance of host age and sex to patterns of reinfection with Ascaris lumbricoides following mass anthelmintic treatment in a South Indian fishing community

Analysis of egg and worm counts of Ascaris recorded at various intervals following a mass anthelmintic treatment programme in a South Indian fishing community is presented. Three indices of infection in the community are compared, namely the prevalence and intensity of egg output (at 2, 6 and 11 months following treatment) and the number of worms expelled following an 11 month period of reinfection. Detailed examination of these measurements revealed significant associations with patient sex and age. The age-prevalence profile of Ascaris infection changed little over time (except immediately following treatment) with the peak prevalence found in the 5–9 year age group. Although 85% of both males and females harboured Ascaris initially, the prevalence following 11 months reinfection was decreased, due to a significantly lower proportion of males being reinfected. By the 11th month of reinfection, the age-intensity profiles of egg output were similar to those observed at initial treatment in the older age groups (10 years and above) and in male children (< 10 years). However, a dramatic increase in the egg output of female children, greatly exceeding the initial mean, was observed within a 6 month period of reinfection. The intensity of egg output did not accurately reflect the abundance of Ascaris recovered via drug-induced expulsion following an 11 month period of reinfection. Although the egg output attained pre-intervention levels, the average worm intensity reached only half the initial value. The trends in the sex- and age-intensity profiles were consistent at the two sampling dates and showed similar patterns to the egg output curves. The relevance of the results to helminth control and the monitoring of reinfection is discussed.</p

Reversal of biliary tract abnormalities associated with opisthorchis viverrini infection following praziquantel treatment

We recently demonstrated a number of biliary tract abnormalities associated with moderate to heavy Opisthorchis viverrini infection among 95 selected village residents in north-east Thailand, who were treated with praziquantel immediately after initial examination and re-examined by abdominal ultrasonography 10 months later. Dramatic improvement in the gall-bladder status of previously infected individuals was observed, including reduction of gall-bladder length and width and regained contractibility of the organ following fatty meal consumption. The frequency of severe enhanced portal vein radicle echoes and gall-bladder sludge and wall irregularities also decreased following treatment, but persisted in many individuals. Two masses were observed in the right hepatic lobe of one individual who was previously considered normal. The findings suggest that gall-bladder abnormalities are reversible following elimination of liver fluke infection, but malignancies, once initiated, are not likely to be affected by treatment.</p

Molecular analysis of T and B cell repertoires in mice immunized with Opisthorchis viverrini antigens

B10 mice were immunized with an Opisthorchis viverrini somatic extract and then their responses were analyzed. The antigenic fractions of the extract were separated by SDS-polyacrylamide gel electrophoresis, electroblotted to nitrocellulose membranes and solubilized for use in lymphocyte culture. Antibody specificity was also visualized by immunoblotting using immunized mouse sera. The Mr of the main immunogenic fractions for T cells ranged from 28 to 46 kDa, whereas those recognized by antibodies were 45, 52, 56, 59, 65, 69, 75 and 81 kDa. The results indicate a striking difference in the antigenie recognition pattern of T and B cells which may be important for selecting antigen molecules for immunological studies of this trematode infection in man.</p

The antibody recognition profiles of humans naturally infected with Ascaris lumbricoides

Summary A semi–quantitative analysis of individual human antibody responses to larval Ascaris excretory and secretory (ES) antigens using radioimmunoprecipi–tation and SDS–PAGE is presented. A significant relationship was observed between the intensity of antibody–precipitated radiolabeled ES antigens and host age. The antibody response profile followed a similar age–related pattern to that of intensity of infection, with blood samples from 5–9–year–old children showing the strongest banding patterns and the heaviest infections. These findings support the hypothesis that the degree of exposure to infective stages of Ascaris is a major determinant of the convex age–intensity profile observed in the community. Considerable heterogeneity was observed in the antibody profiles of individuals, particularly in the recognition of a 14 kD molecule. Positive correlations were observed between the strength of banding at several mol. wts and the worm burdens of individuals. However, the sample size was too small to determine whether these relationships simply reflect age–related profiles or represent independent associations between antibody levels and worm burden. When the data were stratified by age, negative associations between the strength of recognition of some bands and the intensity of infection were suggested and require further study.</p

Parasite-associated morbidity: Liver fluke infection and bile duct cancer in Northeast Thailand

Parasite-associated mortality: liver fluke infection and bile duct cancer in Northeast Thailand. International Journal for Parasitology 24: 833-843. Infection with the liver fluke, Opisthorchis viverrini, remains a major public health problem in Northeast Thailand, where approximately one-third of the population is infected. The northeast region is largely populated by Laos-descendent Thais who enjoy eating raw fish, which harbour the infective stage of the fluke. The parasite has maintained its presence in the population despite the widespread use of praziquantel and dissemination of health education material throughout the region by vigorous government-sponsored programs in recent years. The most severe consequence of liver fluke infection is cholangiocarcinoma, i.e. cancer of the bile duct epithelium. Although mortality due to the parasites alone appears to be uncommon, cholangiocarcinoma arising as a result of infection is one of the leading causes of death in the region.This paper reviews the pathogenesis of infection and the geographic, hospital-based and community studies which demonstrate the close relationship between infection and cancer. In addition, data from the Cancer Registry of Khon Kaen, Northeast Thailand and population-based studies using ultrasonography to visualize early tumours which illuminate the very high frequency of the cancer among heavily infected individuals and communities are discussed. Finally, the paper will close with a brief commentary on the prospects for control of the parasite and its likely impact on the frequency of cancer given the current epidemiological situation of liver fluke infection.</p

Cross-sectional study of Opisthorchis viverrini infection and cholangiocarcinoma in communities within a high-risk area in northeast Thailand

We describe an innovative strategy to quantify risk of cancer associated with varying levels of exposure to chronic parasitic infection through the identification of asymptomatic cases of cholangiocarcinoma within a population‐based survey of Opisthorchis viverrini infection. Stool samples from 12,311 adults over age 24 years from 85 villages in northeast Thailand were examined for intensity of liver fluke infection. People from varying egg count categories were selected for ultrasound examination to identify hepatobiliary disease. Fifteen preclinical cases of cholangiocarcinoma were diagnosed from a total of 1,807 people based on ultrasonographic evidence with confirmation by endoscopy where possible. The prevalence odds of the diagnosis of cholangiocarcinoma increased gradually within the light and moderate intensity groups. In contrast, sharply elevated prevalence odds [age‐, sex‐ and licality‐adjusted prevalence odds ratio (POR) 14.1, p < 0.05] were observed within the most heavily liver fluke‐infected group compared with the uninfected group. Males were more frequently affected than females (crude POR 4.5), but after controlling for intensity of infection, age and locality, the magnitude and significance of this measurement was reduced. Our data clearly demonstrate a significant relationship between intensity of liver fluke infection and cholangiocarcinoma and a strikingly high prevalence of the disease among heavily infected males. © 1994 Wiley‐Liss, Inc.</p

A high frequency of hepatobiliary disease and suspected cholangiocarcinoma associated with heavy Opisthorchis viverrini infection in a small community in north-east Thailand

A group of 87 adults from a small village in north-east Thailand was chosen to undergo ultra-sound investigation based on their intensity of infection with the liver fluke, Opisthorchis viverrini, or clinical status (history of jaundice, current hepatomegaly). From this group, 8 cases of suspected early cholangiocarcinoma were found, and the diagnostic features of 6 of the 8 were confirmed by computerized tomography scan and endoscopic retrograde cholangiopancreatography. In addition, several cases of mild gall-bladder disease, chronic cholecystitis, cholelithiasis and parenchymal liver disease were detected. A highly significant positive relationship between the intensity of liver fluke worm burden and the severity of biliary tract disease within individuals is reported. These results indicate that Opisthorchis is associated with moderate to severe hepatobiliary disease in a considerable proportion of infected individuals.</p

Thiocyanate-independent nitrosation in humans with carcinogenic parasite infection

Infection with the liver fluke, Opisthorchis viverrini, is a causative agent of cholangiocarcinoma. One possible contributing factor in this carcinogenesis is the chronic, local generation of nitric oxide by inflammatory cells expressing inducible nitric oxide synthase and the production of N-nitroso compounds via the reaction between amines and nitrosating agents derived from nitric oxide. Our previous studies provided evidence that nitric oxide synthesis is elevated during human liver fluke infection. Here we present data on the same sample of men which definitively demonstrates increased nitrosation of proline and thioproline (thiazolidine-4-carboxylic acid) among infected men compared to uninfected control subjects on a low nitrate diet. This difference was specifically abolished by co-administration of ascorbic acid with proline and by elimination of parasites by praziquantel treatment. Multivariate statistical models demonstrate the importance of salivary thiocyanate levels to variation in the nitrosation of proline among uninfected individuals, but not among those with current fluke infection. This suggests that considerable generation of nitrosating agents (NO/NO) in infected people may be occurring via oxidation of arginine by nitric oxide synthase in inflamed tissue which is thiocyanate insensitive. Analyses revealed positive associations between N-nitrosoproline excretion and nitrate/nitrite levels in urine, plasma and saliva and with usual alcohol intake; with variation in these trends between groups. In conclusion, we have confirmed the relationship between O.viverrini infection and enhanced endogenous nitrosation, showing evidence of its extragastric site. New information is also provided on the determinants of N-nitrosamino acid excretion in men on a controlled low nitrate diet without smoking, conditions which reduce exogenous sources of nitrosating agents