Short report: low-level lead exposure does not increase the blood pressure in the general population. Cadmibel Study Group.

OBJECTIVE: Long-term exposure to high concentrations of lead may adversely affect several organ systems, but the possible influence of low-level lead exposure on blood pressure remains debatable. The present study examined this relationship in a cross-sectional population survey. METHODS: Blood pressure and lead exposure were measured in 1648 subjects (827 males, 821 females; mean age 45 years), drawn at random from the general population, but not being treated for hypertension. RESULTS: Systolic/diastolic blood pressure averaged 131/77 mmHg in the males and 124/74 mmHg in the females. Blood lead was higher in males than in females (0.5 versus 0.3 mumol/l), but the opposite was observed for zinc protoporphyrin (1.0 versus 1.1 micrograms/g haemoglobin). After adjustment for significant covariates (age, body mass index, pulse rate, serum creatinine and serum calcium, and for contraceptive pill intake and menopause in females), systolic pressure was negatively correlated with blood lead in males; the partial correlations with blood lead were not significant for systolic pressure in females nor for diastolic pressure in either sex. Neither males nor females showed a significant relationship between blood pressure and lead exposure assessed from the zinc protoporphyrin level in blood. CONCLUSIONS: This study does not support the hypothesis that exposure to lead is associated with increased blood pressure in the population at large.

Characterization of cadmium proteinuria in man and rat.

In workers chronically exposed to cadmium and without signs of renal insufficiency, plasma proteins with molecular weight ranging from 11,800 to 450,000 are excreted in greater amount in urine. Increased urinary excretion of low and high molecular weight proteins can occur independently. Because of its greater stability in urine and provided a sensitive immunological technique is used, the determination of retinol-binding protein is a more practical and reliable test of proximal tubular function than beta 2-microglobulin. The evaluation of renal function of workers removed from cadmium exposure indicates that cadmium-induced renal lesions, albeit of slow progression, are not reversible when exposures ceases. In workers chronically exposed to cadmium or removed from cadmium exposure, metallothionein in urine is directly correlated with cadmium in urine but not with cadmium in blood or years of cadmium exposure. The association between cadmium in urine and metallothionein in urine is independent of the status of renal function and the intensity of current exposure to cadmium. Whereas the repeated IP injection of high doses of cadmium to rat gives rise to a mixed or tubular type proteinuria, the prolonged oral administration of cadmium results mainly in the development of a glomerular type proteinuria. The former is usually reversible after cessation of treatment whereas the latter is not. Circulating antiglomerular basement membrane antibodies have been found in man and in rat chronically exposed to cadmium. The pathogenic significance of this finding deserves further investigation.

Investigations on the lung and kidney function in workers exposed to cadmium.

The kidney seems more sensitive to the chronic effect of cadmium than the lung. Only minor impairments of lung function (mild form of obstructive lung disease) were found after long-term occupational exposure (less than 20 yr) to moderate concentration of cadmium oxide dust and fume. This conclusion, cannot, however be extrapolated to acute or subacute inhalational exposure. The nephrotoxicity of cadmium consists in a tubular dysfunction characterized by an increased excretion of beta 2-microglobulin and giving rise to the classical tubular proteinuria and in a glomerular dysfunction evidenced by an increased excretion of high molecular weight proteins and increased levels of beta 2-microglobulin and creatinine in plasma and giving rise to a glomerular type proteinuria. These renal changes were mainly found in workers whose cadmium concentration at time of the survey exceeded 1 microgram Cd/100 ml in blood and 10 microgram Cd/g creatinine in urine. It should, however, be stressed that higher levels of Cd in blood and in urine are not necessarily associated with the presence of excessive proteinuria. In newly exposed workers, the Cd level in blood increases progressively to a plateau after several weeks. Cadmium level in urine fluctuates more. In workers exposed for several months to an airborne concentration exceeding 200 microgram/m3, Cd concentration in urine seems mainly influenced by recent exposure.

Investigations of factors influencing exposure and response to lead, mercury, and cadmium in man and in animals.

The susceptibility of the heme biosynthetic pathway to lead, as reflected by increased free erythrocyte porphyrin (FEP) concentration, is in humans as well as in rats in the order of young greater than or equal to female greater than male. The difference between adult male and female rats can be explained at least partially by the interaction of estradiol and progesterone with the FEP response to lead; the hormonal influence on FEP does not seem to be mediated through changes in plasma iron. The classical "tubular type" proteinuria in workers chronically exposed to cadmium has two not necessarily concomitant components, namely, a tubular type and a glomerular type component characterized by increased excretion of low and high molecular weight proteins, respectivley. No synergistic effect of cadmium and lead on the proteinuria of workers simultaneously exposed to both metals was observed. Mercury (most likely methylmercury) is freely transferred from the mother to the fetus; there is only a slight placental barrier for lead and a rather strong one for cadmium. Compared to maternal blood, placenta does not accumulate lead or mercury but concentrates cadmium about 10-fold.

Urinary protein 1 or Clara cell protein: a new sensitive marker of proximal tubular dysfunction.

Protein 1 or Clara cell protein (CC16) is a 16 kD protein secreted predominantly by Clara cells in terminal bronchioles and from puberty on in the male urogenital tract. The sensitivity of CC16 in urine as an index of proximal tubule dysfunction was compared to that of retinol-binding protein, beta 2-microglobulin and alpha 1-microglobulin. These microproteins were measured by latex immunoassay in the urine from 114 pregnant women, 126 diabetics (65 men and 61 women), 80 workers exposed to cadmium (36 men and 44 women), and from healthy subjects matched for age and sex. In women, CC16 appeared consistently as a much more sensitive index of tubular dysfunction than other microproteins. In female diabetics, for instance, the prevalence of elevated values of CC16 in urine (53%) largely exceeded that of other microproteins (< 30%) and even of albumin (35%). In men, however, the existence of a post-renal secretion contaminating the urine limits the sensitivity of CC16 which was revealed to be higher than that of other microproteins, in diabetics only. The assay of urinary CC16 has the potential, especially in women, to detect very subtle defects of the proximal tubule which pass completely unseen with other microproteins. We postulate that this unique sensitivity of CC16 is due to its very low concentration in tubular fluid which, combined with its anionic character, strongly hinders its access to brush border binding sites.

Low-level lead exposure and blood pressure.

The possible association between low-level lead exposure and blood pressure (BP) remains debated. The purpose of this review was: (1) to determine whether the available studies in humans support a positive association, in particular at lower exposure levels (blood lead concentration < 1 mumol/l), and (2) to explore whether animal studies and the proposed pathophysiological mechanisms are supportive of a positive and causal association between lead exposure and hypertension. A meta-analysis of 23 studies included 33,141 subjects recruited from the general population in 13 surveys and from occupational groups in 10 studies. In all but four studies the results had been adjusted for age, and most studies also considered additional confounders. The association between BP and blood lead was similar in both sexes. In all 23 studies combined, a two-fold increase in blood lead concentration was associated with a 1 mm Hg rise in the systolic pressure (CI 0.4-1.6 mm Hg; P = 0.002) and with a 0.6 mm Hg increase in the diastolic pressure (CI 0.2-1.0 mm Hg; P = 0.02). Of 21 animal studies, one was carried out in dogs, one in pigeons and the remainder in various rat strains. In 15 studies, in which the lead dose in drinking water or food exceeded 1 p.p.m. the association between BP and exposure was found to be positive in seven, inconsistent in three, absent in four and negative in one. Of the six studies at lower exposure levels (< or = 1 p.p.m.), five found a pressor effect attributable to lead. Whether the lead doses in the animal studies are equivalent to the human exposure levels and to what extent one can extrapolate from genetically heterogeneous animals to humans, remains doubtful. If a causal relation between lead exposure and hypertension exists, the proposed mechanisms may include interference of lead with ion transport across cell membranes, interactions with calcium homeostasis and calcium-mediated processes, direct vasomotor actions and the potentiation of sympathetic stimulation. Interference of lead with the balance between the renin-angiotensin-aldosterone and the kallikrein-kinin systems and impairment of renal function are unlikely to be implicated. On balance, the published evidence suggests that there can only be a weak positive association between BP and lead exposure. The latter relation, which is barely visible at the horizon of epidemiological observation, may not be causal in nature and is unlikely to entail any public health implication in terms of hypertension-related complications.

Dimethylformamide (DMF) hepatotoxicity.

Scattered case reports of accidental exposure and a few epidemiological studies have indicated that the liver is the main target organ following acute and chronic exposure to dimethylformamide (DMF). This has been confirmed in several animal species. In humans, ethanol intolerance is one of the earliest manifestations of (excessive) exposure to DMF, followed at higher exposure levels by various complaints (nausea, vomiting, abdominal pain) and the release of liver cytolytic enzymes in the plasma. The metabolic pathway of DMF has been recently clarified, but the primary cellular lesion responsible for its hepatotoxicity is still unknown.

Influence of 2,3-dimercaptopropane-1-sulfonate and dimercaptosuccinic acid on the mobilization of mercury from tissues of rats pretreated with mercuric chloride, phenylmercury acetate or mercury vapors.

The efficiency of the sodium salt of 2,3-dimercaptopropanesulfonic acid (DMPS) and meso-dimercaptosuccinic acid (DMSA) to mobilize mercury from tissues has been assessed in rats pretreated with different doses of HgCl2, phenylmercury acetate or exposed to different concentrations of mercury vapors. These pretreatments increase the mercury concentration in the kidney and to a lower extent in the liver. Only exposure to metallic mercury vapor leads to mercury accumulation in the brain. Both chelators mobilize mercury stored in the kidney and the amount of metal excreted in urine following a single administration of DMSA is a good indicator of the renal burden of mercury. The rate of removal is greater after DMPS administration than after DMSA but repeated administration of either agents eventually leads to the same total amount of mercury mobilized from the kidney. The loss of mercury from the liver can be slightly accelerated by repeated administration of the chelators. However, the chelators are inefficient in removing mercury from the brain.

Gentamicin nephrotoxicity in cadmium, lead and mercury pretreated rats.

The effect of a previous chronic exposure to cadmium, lead or inorganic mercury on the nephrotoxic potential of gentamicin was investigated in female Sprague-Dawley rats. A daily dose of 10 mg gentamicin/kg body weight/day was administered for 21 days to rats having a renal load of 168 micrograms Cd, 35 micrograms Pb or 129 micrograms Hg/g whole kidney. Urine analysis suggests an attenuation of the nephrotoxic potential of gentamicin while a microscopical examination of kidneys indicates a superimposition of the effects of the metals and the antibiotics. The only clear interaction observed consists in a reduction of gentamicin accumulation in the cortex of cadmium-treated animals. It is concluded that none of the metal pretreatments potentiates the nephrotoxic effects of gentamicin.

Comparison, by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, of urinary proteins excreted by workers exposed to cadmium, mercury or lead.

Urinary proteins from workers exposed to cadmium (Cd, n = 20), lead (Pb, n = 19) or mercury (Hg, n = 25) were analyzed by polyacrylamide gel electrophoresis (PAGE) in the presence of sodium dodecyl sulfate (SDS). The areas of the peaks with the relative mobilities of beta 2-microglobulin and retinol binding protein (low molecular weight proteins), albumins, transferrin and IgG (high molecular weight proteins) were measured and compared with those obtained in matched control groups. The concentrations (mean and range) of the metals in blood (B, micrograms/100 ml) and in urine (U, micrograms/g creatinine) of the exposed groups were as follows: Cd group, CD-B = 1.51 (0.18-4.31) and CD-U = 16.6 (2.08-59.3); Pb group, Pb-B = 44.5 (44.8-61.3) and Pb-U = 88.7 (15.2-298); Hg group, Hg-B = 3.74 (1.84-8.14) and Hg-U = 116 (51.8-206). The average duration of exposure to the metal was 30.5 (Cd), 12.5 (Pb) and 7.2 (Hg) years respectively. Under these exposure conditions, it was found that Cd increases the urinary excretion of low as well as high molecular weight proteins, Hg induces an increased urinary excretion of only high molecular weight proteins and lead has no significant effect on the renal excretion of either type of protein.

Health risk assessment of long-term exposure to non-genotoxic chemicals: application of biological indices.

For chemical pollutants, health risk assessment of long-term exposure is usually best realized through an epidemiologic approach which attempts to link cumulative levels of exposure to the potential for occurrence of early adverse effects. For some chemicals, however, the frequency of peak exposures may be more relevant for assessing the health risk than the integrated dose. In very few circumstances, biological exposure indices directly reflect the cumulative dose (e.g. PCB in blood). More frequently they are indicators of short-term interval dose but provided they have been measured with a sufficient frequency, their integration over the duration of exposure may represent a valid surrogate of the cumulative dose. This has been clearly demonstrated for lead or cadmium in blood. The selection of the appropriate biological effect markers for the study of the dose-effect/dose-response relationships is frequently a controversial issue when information on the mechanism of action of the pollutant is insufficient. In this case, the study of the health significance of the observed biological changes may be required for assessing a meaningful no-adverse-effect level. For example, in adult male workers moderate exposure to lead may affect the synthesis of vasodilatory prostaglandins in the kidney but presently there is no indication that this effect should be taken into account to define the acceptable occupational exposure level to lead because it is not associated with an impairment of the hemodynamic response of the kidney to an acute protein load. On the contrary, a low-molecular-weight proteinuria induced by cadmium may be predictive of an increased age-related decline of the glomerular filtration rate. Although the use of early biological effect markers for the study of the dose-effect or dose-response relationships in humans is probably less affected by selection biases than morbidity data, the possibility of such an interference cannot be excluded. For example, in the general population, the tubulotoxic effects of cadmium may occur at a lower body burden of the metal than in adult male workers. Whatever the adverse biological effect considered, the application of an uncertainty factor remains justified when extrapolating a no-effect level from adult male workers to the general population.

Evaluation of the subacute nephrotoxicity of cyclohexane and other industrial solvents in the female Sprague-Dawley rat.

The subacute nephrotoxicity of more than 20 industrial solvents has been compared in female Sprague-Dawley rats. The animals were given 5 i.p. injections of the solvents per week for 2 weeks at doses ranging from 1/20 to 1/5 of the i.p. or oral LD50 and the urinary excretion of N-acetyl-beta-D-glucosaminidase, beta 2-microglobulin and albumin was determined. Under these experimental conditions, two solvents, cyclohexane and styrene, were found to cause some tubular injury as evidenced by a statistically significant increase of beta 2-microglobulinuria. At the same dose, styrene was more tubulotoxic than cyclohexane but the opposite was observed when the solvents were administered proportionally to their LD50. The increased beta 2-microglobulinuria caused by cyclohexane was both time- and dose-dependent. It was not accompanied by changes in the glomerular filtration rate and the renal plasma flow, but at the highest dose (1.5 g/kg) the renal concentrating ability was depressed. These renal tubular effects can most likely be ascribed to cyclohexanol, the main metabolite of cyclohexane. As cyclohexane is a widely used industrial solvent with a relatively high threshold limit value (TWA-TLV: 300 ppm) it might represent an underestimated risk for the renal function of exposed populations.

Carcinogenicity and mutagenicity of chromium.

Occupational exposure represents the main source of human contamination by chromium. For non-occupationally exposed people the major environmental exposure to chromium occurs as a consequence of its presence in food. Chromium must be considered as an essential element. Its deficiency impairs glucose metabolism. Trivalent chromium salts are poorly absorbed through the gastro-intestinal and respiratory tracts because they do not cross membranes easily. Hexavalent chromium can be absorbed by the oral and pulmonary routes and probably also through the skin. After its absorption, hexavalent chromium is rapidly reduced to the trivalent form which is probably the only form to be found in biological material. Epidemiological studies have shown that some chromium salts (mainly the slightly soluble hexavalent salts) are carcinogens. Lung cancers have, indeed, often been reported among workers in chromate-producing industry and, to a lesser extent, in workers from the chrome-pigment industry. The first attempts to produce cancers in experimental animals by inhalation or parenteral introduction gave negative or equivocal results but, from 1960, positive results have been obtained with various chromium compounds. As for the carcinogenic activity, the mutagenicity of chromium has mainly been found with hexavalent salts. In the majority of assay systems used, trivalent chromium appears inactive. It can be considered as evident, however, that the ultimate mutagen which binds to the genetic material is the trivalent form produced intracellularly from hexavalent chromium, the apparent lack of activity of the trivalent form being due to its poor cellular uptake.

Carcinogenicity, teratogenicity and mutagenicity of arsenic.

Arsenic may be released into the environmental through industrial processes and through the generation of power from coal. It is also widely used in agriculture and was formerly used extensively in medicine. For the general population, exposure to arsenic occurs mainly through the ingestion of foodstuffs containing inorganic and organic arsenicals. Trivalent arsenicals are regarded as being primarily sulfhydryl reagents with the result they inhibit a number of thiol-dependent enzymic systems in various tissues. Arsenite also has an effect on DNA synthesis and DNA repair. Owing to its lower affinity for hydroxy and thiol groups, pentavalent arsenate inhibits fewer enzymic systems. Although there is no reliable evidence that arsenic produces tumors in experimental animals, epidemiological studies show that the incidence of epidermoid carcinomas of the skin and lungs, and of pre-cancerous dermal keratoses, is significantly increased in human subjects who have been chronically exposed to arsenic compounds by oral or respiratory routes. Arsenic appears to be one of the only teratogenic members of the Group V metals. Most of the studies performed on the mutagenic activity of arsenic have provided positive results. They involve experiments on microorganisms, plant material and Drosophila as well as observations on the ability of this metal to induce, in vitro and in vivo, chromosomal aberrations in mammalian cells.

Mutagenicity and teratogenicity of mercury compounds.

Agriculture, consumption of fossil fuels and, to a lesser extent, industry, are the main sources of pollution by mercury which is discharged into the environment as metallic mercury, as inorganic mercury compounds, or as organic compounds. Once in the environment, mercury compounds are capable of a variety of transformations. Some professional or accidental mercury poisonings have been reported in human populations, but they can easily be minimized by appropriate preventive measures. Production of C-mitosis in plant material is the most noticeable genetic effect of mercury compounds. No positive report that mercury could be carcinogenic in man has appeared up to now and animal experiments have also provided negative results. Although placenta may represent a certain barrier to mercury, embryotoxicity and teratogenicity of organic mercury compounds have been observed in numerous systems such as fish, birds and mammals.

[Occupational health in Belgium]. / La médecine du travail en Belgique.

The author describes briefly the state of occupational health in Belgium. The organization and the activities of occupational health services and the legislation regarding the compensation of work accident and occupational diseases are first outlined. The training of occupational physicians in medical schools is also described as well as the trend of research activities in occupational health in Belgium.

Impact of environmental cadmium pollution on cadmium exposure and body burden.

The body burden of cadmium, as estimated from 24-h urine cadmium levels, was determined in 1,523 subjects who were not occupationally exposed and who lived in five areas of Belgium. Urinary cadmium levels differed significantly with place of residence. These differences persisted after standardization for the other significant determinants (i.e., age, body mass index, smoking habits, social class, alcohol consumption, and menopause). The highest 24-h urine cadmium levels were found in subjects who lived in areas that contained cadmium-polluted soils. The body burden overload has been attributed mainly to the consumption of locally grown vegetables and the use of contaminated well water for cooking and drinking. Blood cadmium levels were also dependent on place of residence. However, the geographical differences in blood cadmium did not parallel those of urine cadmium. Blood cadmium is more influenced by recent exposure; therefore, this latter observation might reflect the recent implementation of preventive measures in some areas.