Epidemiological survey of workers exposed to inorganic germanium compounds.

OBJECTIVES: To assess occupational exposure to inorganic germanium (Ge) in workers from a producing plant, and to assess the health of these workers, with a special focus on respiratory, kidney, and liver functions. METHODS: Cross sectional study of 75 workers exposed to Ge and 79 matched referents. Exposure was characterised by measuring air and urine concentrations of the element during a typical working week, and health was assessed by a questionnaire, clinical examination, lung function testing, chest radiography, and clinical chemistry in serum and urine, including high and low molecular weight urinary proteins. RESULTS: Airborne concentrations of Ge (inhalable fraction) ranged from 0.03 to 300 micrograms/m, which was reflected by increased urinary excretion of Ge (0.12-200 micrograms/g creatinine, after the shift at the end of the working week). Lung, liver, and haematological variables were not significantly different between referents and workers exposed to Ge. A slightly higher urinary concentration of high molecular weight proteins (albumin and transferrin) was found in workers exposed to Ge, possibly reflecting subclinical glomerular changes. No relation was found between the intensity or duration of exposure and the urinary concentration of albumin. No difference between referents and workers exposed to Ge was found for other renal variables. CONCLUSIONS: Measurement of urinary Ge can detect occupational exposure to inorganic Ge and its compounds. It is prudent to recommend the monitoring of renal variables in workers exposed to Ge.

Hematopoietic and lymphatic malignancies in vehicle mechanics.

Although it is generally acknowledged that benzene causes leukemia, especially acute myeloid leukemia, considerable divergences persist in the assessment of the leukemia risk due to occupational low-level benzene exposure. Specifically, the risk for vehicle mechanics is considered by some authors as being nondetectable with epidemiologic methods, whereas others calculated that the incidence rate of leukemia (all types) in vehicle mechanics is increased more than 60 times. The purpose of this review is to examine the publications on this topic in light of criteria for causal inference and to discuss the possible role of bias, confounding factors, and chance. The results of this analysis reveal that there are surprisingly few epidemiologic observations supporting an increased incidence of leukemia in vehicle mechanics. Apparently, publications suggesting a leukemogenic effect of low-level benzene exposure in garage mechanics are more often quoted than their negative counterparts, although they are not better designed.

The assessment of biomarkers to detect nephrotoxicity using an integrated database.

Groups of industrial workers exposed to heavy metals (cadmium, mercury, and lead) or solvents were studied together with corresponding control groups. The cohorts were collected from several European centers (countries). Eighty-one measurements were carried out on urine, blood, and serum samples and the results of these analyses together with questionnaire information on each individual were entered into a central database using the relational database package Rbase. After the completion of the database construction phase, the data were exported in a format suitable for analysis by the statistical package SAS. The potential value of each test as an indicator of nephrotoxicity was then assessed. Rigorous exclusion criteria were applied which resulted in the elimination of some tests and samples from the dataset. The measurable contributions of smoking, gender, metal exposure, and site were either singly or in combination assessed by biomarkers for nephrotoxicity. The parameters measured included three urinary enzymes, six specific proteins, total protein, two extracellular matrix markers, four prostaglandins and anti-GBM antibodies, and beta 2-microglobulin in serum. The most sensitive renal tests included the urinary enzymes N-acetyl-beta-D-glucosaminidase (NAG) and intestinal alkaline phosphatase (IAP), brush border antigens, and urinary low-molecular-weight proteins. Of the newer tests investigated the prostaglandins were the most promising. Different patterns of biomarker excretion were observed following exposure to lead, cadmium, or mercury. The dataset provides a unique repository of data which could provide the basis of an enlarging source of information on normal human reference ranges and on the effects of exposure to toxins and the use of biomarkers for monitoring nephrotoxicity.

Reversibility of microproteinuria in cadmium workers with incipient tubular dysfunction after reduction of exposure.

The study aimed at assessing the evolution of cadmium (Cd)-induced renal tubular dysfunction in Cd workers according to the severity of the microproteinuria observed at the time the exposure was substantially decreased. Male workers employed in the Cd production industry for whom formerly high exposure had markedly decreased by 1984 and for whom standardized medical data were available during two observation periods (1980-1984 and 1990-1992) were eligible for the study. A total of 32 Cd workers fulfilling this profile were divided into two groups on the basis of historical records of urinary Cd concentration (Cd-U) covering the period until 1984. The workers with Cd-U values of > 10 micrograms Cd/g creatinine were subdivided further on the basis of the urinary concentration of beta 2-microglobulin (beta 2 MG-U) measured during the first observation period (1980-1984). In each group, the tubular microproteinuria as reflected by beta 2 MG-U and the concentration of retinol-binding protein in urine as well as the internal Cd dose as reflected by the concentration of Cd in blood and urine were compared between the first and second (1990-1992) observation periods. Increased microproteinuria was often diagnosed in cases with Cd-U values of > 10 micrograms Cd/g creatinine. The evolution of tubular renal function has been found to depend on the extent of the body burden of Cd (as reflected by Cd-U) and the severity of the initial microproteinuria at the time high Cd exposure was reduced or ceased. When reduction of Cd exposure took place while beta 2 MG-U did not exceed the upper reference limit of 300 micrograms/g creatinine, the risk of developing tubular dysfunction at a later stage was likely to be low, even in cases with historical Cd-U values occasionally > 10 but always < 20 micrograms Cd/g creatinine. When the microproteinuria was mild (beta 2 MG-U > 300 and < or = 1,500 micrograms/g creatinine) at the time exposure was reduced, and the historical Cd-U values had never exceeded 20 micrograms Cd/g creatinine, there was indication of a reversible tubulotoxic effect of Cd. When severe microproteinuria (beta 2 MG-U > 1,500 micrograms/g creatinine) was diagnosed in combination with historical Cd-U values exceeding 20 micrograms Cd/g creatinine, Cd-induced tubular dysfunction was progressive in spite of reduction or cessation of Cd exposure.

Proximal tubular injury in Chinese herbs nephropathy: monitoring by neutral endopeptidase enzymuria.

Neutral endopeptidase (NEP) is a 94 kDa ectoenzyme of the proximal tubule brush border, physiologically released into the urine with apical membrane fragments. As proximal tubular atrophy was a histological hallmark of Chinese herbs nephropathy (CHN), this study firstly determined renal excretion of NEP in healthy control subjects (N = 31), in patients with CHN (N = 26) and in women having consumed Chinese herbs and whose renal function was normal but running the risk of developing CHN (N = 27). Another patient group consisted of female patients with glomerular diseases (N = 12). At the same time, measurements of urinary microproteins (Clara cell protein, retinol binding protein, beta 2-microglobulin and alpha 1-microglobulin) were performed, as indicators of tubular dysfunction. Cell damage was estimated by the excretion of N-acetyl-beta-D-glucosaminidase (NAG). In the control group, the physiological NEP enzymuria was 43.1 micrograms/24 hr (geometric mean). In CHN patients, levels of urinary NEP were significantly decreased in those with moderate renal failure (26.7 micrograms/24 hr; N = 21; P < 0.05) and almost abolished in end-stage renal failure patients (4.35 micrograms/24 hr; N = 5; P < 0.05). In patients at risk as well as in patients with glomerular diseases, urinary NEP levels were not statistically different from those observed in control subjects (40.68 micrograms/24 hr and 48.5 micrograms/24 hr, respectively). Several degrees of tubular dysfunction and injury were noted in patients groups, as attested by increased urinary microproteins and NAG excretions. Considering the data from control and CHN patients, NEP enzymuria positively correlated with individual creatinine clearance values (r = 0.76; P = 0.0001) and negatively correlated with urinary microproteins levels (r = -0.55; P = 0.00001). Finally, NEP was regularly quantitated in the urine of 6 CHN patients for a period ranging from six months to two years and in 19 patients at risk during two years, respectively. In the first group, renal function progressively deteriorated in 3 patients, leading them to renal replacement therapy after 38 to 115 weeks. Stable parameters were observed in the remaining 3 patients. A direct correlation between creatinine clearance and NEP excretion was found longitudinally in each case. In the second group, no significant change of urinary NEP levels was observed (45.9 micrograms/24 hr), in parallel with stable renal function. Taken together, these results indicate that, in CHN patients, NEP enzymuria provides a rapid and noninvasive determination of the degree of structural impairment affecting the proximal tubular population and further reflecting the severity of the renal disease. The interest of this urinary marker in monitoring the progression of other tubulointerstitial diseases remains to be assessed.

Long-term pulmonary and systemic toxicity following intravenous mercury injection.

Long-term pulmonary and systemic toxicity following mercury intravenous injection has rarely been assessed. We present the results of a detailed investigation assessing pulmonary and systemic long-term toxic effects in a subject who had pulmonary and systemic mercury microembolism diagnosed more than 11 years previously. Radiographic examination showed the persistence of mercury microemboli in both lungs and elsewhere in the body. Lung function tests revealed a decreased diffusing capacity for carbon monoxide and PO2 probably indicative of microscopic inflammation of lung interstitium. Electroneuromyography showed signs of mild axonopathy in both legs. At semen analysis, a high proportion of motionless spermatozoa was present. Urinary excretion of mercury was high. Signs of interstitial lung impairment, peripheral axonopathy and asthenozoospermia in a subject who had mercury microembolism persisting for more than 11 years might be evidence of long-term mercury toxicity.

Effect of oral protein load on urinary protein excretion in workers exposed to cadmium and to lead.

An acute oral protein load causes a transient hyperfiltration that might reveal a loss of glomerular permselectivity properties. The effect of an oral protein load on the urinary excretion rate of albumin (UAE), beta-2-microglobulin (UB2MGE), and retinol-binding protein (URBPE) was thus examined in cadmium- and lead-exposed workers. The results show a transient increase in UB2MGE and URBPE without relevant changes in UAE. These changes were also observed in control groups and are due to competitive inhibition of tubular protein reabsorption by absorbed cationic amino acids. These results do not support the hypothesis that the acute protein load test is of great utility in revealing a silent glomerular filtration disturbance in lead- or cadmium-exposed workers. However, it might disclose imminent renal tubular dysfunction in cadmium workers not yet showing increased microproteinuria under baseline conditions.

Public health implications of environmental exposure to cadmium and lead: an overview of epidemiological studies in Belgium. Working Groups.

The CadmiBel Study was a cross-sectional population study that investigated the health effects of environmental exposure to cadmium and lead. The 2327 participants constituted a random sample of the population of four Belgian districts, chosen in order to provide a wide range of environmental exposure to cadmium. After adjustment for confounding factors, such as smoking and occupational exposure, the urinary cadmium excretion, a measure of lifetime exposure, was nearly 30% higher in the polluted areas. The CadmiBel Study produced evidence inconsistent with the hypothesis that environmental exposure to cadmium and lead would lead to an increase in blood pressure and to a higher prevalence of hypertension and other cardiovascular diseases. On the other hand, the serum alkaline phosphatase activity and the urinary excretion of calcium were significantly and positively correlated with urinary cadmium in both sexes. These findings suggested that the homeostasis of calcium was gradually affected as cadmium accumulated in the body. Furthermore, several markers of renal tubular dysfunction (urinary excretion of retinol-binding-protein, N-acetyl-beta-glucosaminidase, beta 2-microglobulin and amino acids) were significantly and positively associated with urinary cadmium. Across 10 small areas of which six were polluted with cadmium, an inverse association existed between the creatinine clearance and several indexes of environmental exposure to cadmium (cadmium concentration in the soil, cadmium content of locally grown vegetables, the inhabitants' 24 h urinary cadmium excretion). In the CadmiBel Study, the creatinine clearance was also inversely correlated with the concentrations of lead and zinc protoporphyrin in the blood. Thus, environmental exposure to cadmium and lead was associated with alterations in renal function. The significance in terms of morbidity and mortality of the functional disturbances observed in the CadmiBel Study, and the possible strategies to prevent the transfer of cadmium from the environment to man are under investigation in the prospective PheeCad Study in which half of the Cadmibel participants have been enrolled (participation rate 80%).

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.

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.

Urinary excretion of lead and mercury after oral administration of meso-2,3-dimercaptosuccinic acid in patients with motor neurone disease.

Amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA) are progressive neurodegenerative disorders involving motor neurones. The aetiology of the non-familiar forms is still unknown but it has been suggested that long-term exposure to heavy metals such as lead and mercury may play a role in the pathogenesis of these diseases. In 53 patients suffering from ALS (n = 42) and SMA (n = 9) the oral administration of dimercaptosuccinic acid (DMSA, 20 mg/kg) did not result in a greater mobilization of lead and mercury from peripheral depots than in control subjects. Although it cannot be excluded that the amount of lead or mercury excreted after DMSA administration may not be a reflection of the amount accumulated in the motor neurons, this study does not provide support for the hypothesis that heavy metals play a significant role in the occurrence of motor neurone diseases.

Lung retention and bioavailability of arsenic after single intratracheal administration of sodium arsenite, sodium arsenate, fly ash and copper smelter dust in the hamster.

Arsenic is present in airborne particulate material released by coal-fired power plants and non-ferrous metal smelters. We have assessed whether the physico-chemical properties of arsenic in such particles play a role in its lung retention and uptake by the body. Female hamsters were given a single intratracheal instillation of fly ash or copper smelter dust suspensions (at doses of 50 or 100 µg As kg(-1)) or identical amounts of soluble tri- and pentavalent arsenic, in the presence or absence of an inert dust material (tungsten carbide). The concentration of the element was measured in a 24 hour urine sample collected on the 1st, 2nd and 6th day after treatment and arsenic remaining in lung tissue was determined at the end of the same time periods. Both lung retention and urinary As excretion indicate a prolonged contact of the lung tissue with particulate As in contrast to soluble As salts. In addition to the effect of solubility described here, more research is needed to determine the effect of particle size and lung loading on retention, as well as the potential differences in the lung inflammatory response using arsenic-rich particulates from various sources.

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.

Serum Clara cell protein: an indicator of bronchial cell dysfunction caused by tobacco smoking.

Clara cell protein (CC16) is a 16-kDa protein secreted by Clara cells and other nonciliated cells of both the bronchiolar and bronchial epithelium. CC16 is present in high concentrations in the respiratory tract secretions but occurs also in other fluids such as serum. In this study, CC16 has been measured in the sera from 65 female and 69 male current smokers and in a sex- and age-matched control group of 135 neversmokers. Lifetime smoking averaged (geometric mean) 12.7 (range, 0.6 to 61.3) and 17.9 (range, 0.8 to 126) pack-years in female and male smokers, respectively. A significant reduction of Clara cell protein was found in the sera of smokers of both sexes. In neversmokers serum CC16 was independent of sex but significantly increased with age. In current smokers serum CC16 was also negatively correlated with both the current and lifetime cigarette consumption and with the 24-h urinary excretion of thiocyanate. After adjustment for age, a linear dose-response relation was apparent between smoking history and serum CC16, the latter decreasing on average by about 15% for each 10 pack-year smoking history. The present study supports the concept that CC16 in serum is a marker of bronchial dysfunction caused by tobacco smoke. As CC16 appears to be a natural immunosuppressor of the respiratory tract, its decreased production might explain some inflammatory changes associated with smoking.

Cadmium: exposure markers as predictors of nephrotoxic effects.

Cadmium (Cd) is a cumulative element with a biological half-life of > 10 years in humans. The total amount of Cd accumulated in the liver and in the kidney can be measured in vivo by neutron activation (or x-ray fluorescence), but this technique does not necessarily measure the fraction that is biologically active. At low exposure (i.e., general environmental exposure or moderate occupational exposure), blood Cd is mainly influenced by the last 2 to 3 months of exposure. Under such conditions, the Cd concentration in urine mainly reflects the amount of Cd stored in the body, particularly in the kidney. In Europe and the US, the Cd reference values are usually < 2 nmol/mmol creatinine. Because most of the Cd in urine is probably bound to metallothionein, the changes in the urinary metallothionein concentration parallel those of Cd. The determination of Cd concentration in hair is of limited value because in humans it is difficult to distinguish between externally deposited and endogenous Cd. Fecal Cd is a good indicator of the oral daily intake. The results of several cross-sectional epidemiologic studies of the relation between the prevalence of renal dysfunction and Cd concentration in urine led us to propose a biological limit value for Cd of 5 and 2 nmol/mmol creatine for adult male workers and the general population, respectively.

Hypertension caused by low-level lead exposure: myth or fact?

BACKGROUND: Several reports on the possible association between low-level lead exposure and blood pressure reflect diverging views. This meta-analysis aimed to find a common denominator in the published literature and to estimate whether a relationship exists between blood pressure and levels of lead in the blood. METHODS: Of the studies reviewed, 23 provided sufficient details to be considered. The meta-analysis included 33 groups with a total of 33 141 subjects, who had been recruited from the general population in 13 surveys and from occupational groups in 10 studies. In all but four studies the results were adjusted for age, and most studies took into account additional confounding factors. RESULTS: The association between blood pressure and blood lead was similar in both men and women. In the combined studies, a twofold increase in blood lead concentration was associated with a 1.0 mmHg rise in systolic pressure (confidence interval 0.4-1.6 mmHg; P = 0.002) and with a 0.6 mmHg increase in diastolic pressure (confidence interval 0.2-1.0 mmHg; P = 0.02). The association with systolic pressure strongly relied on the inclusion of a large study (n = 3851) in which women's blood pressure was measured at the end of pregnancy. The association with diastolic pressure was largely due to a population survey in the USA (n = 6289). There was no relationship across studies between the strength of the blood pressure-blood lead relationship and the mean blood lead concentration. CONCLUSION: The published evidence suggests that there can only be a weak positive association between blood pressure and lead exposure. Any such relationship may not be causal and is unlikely to entail any public-health implication in terms of hypertension-related complications. Nevertheless, these assumptions need to be confirmed in prospective population studies.

Renal function and historical environmental cadmium pollution from zinc smelters.

We investigated whether there was an association between renal function and cadmium pollution in areas with different exposures. Cadmium was measured in the soil and in vegetables in 10 districts, 6 of which were close to zinc smelters; and renal function and the concentrations of metals in blood and urine were measured in 703 randomly selected residents. 6 polluted areas, compared with 4 others showed higher cadmium concentrations in the soil (4.86 vs 0.81 ppm) and in locally grown vegetables, such as celery (2.43 vs 0.68 ppm) and beans (0.42 vs 0.15 ppm). Residents in polluted areas had higher urinary cadmium (10.5 vs 7.9 nmol/24 hours) and copper (0.16 vs 0.14 mumol/24 hours); higher serum creatinine (100 vs 97 mumol/L) urinary excretions of beta 2-microglobulin (109 vs 95 micrograms/24 hours), retinol-binding-protein (136 vs 118 micrograms/24 hours), and N-acetyl-beta-glucosaminidase (1.78 vs 1.38 U/24 hours). Serum zinc (12.2 vs 12.6 mumol/L) and creatinine clearance (87 vs 92 mL/min) were reduced in the 6 polluted areas. In all 10 districts, cadmium in the soil was positively correlated with cadmium in celery (r = 0.77), in beans (r = 0.67), and in residents' urine (r = 0.76). The creatinine clearance was inversely correlated with cadmium in soil (r = -0.78), in celery (r = -0.90), and in beans (r = -0.70). Past emissions from zinc smelters gave rise to contamination of the environment with cadmium, which gets into the food chain and has the potential to cause renal dysfunction and alterations in zinc and copper homeostasis.

Is a positive association between lead exposure and blood pressure supported by animal experiments?

The possible association between low-level lead exposure and blood pressure and the causal nature of any such relationship continue to be debated. A recent meta-analysis of the human model data showed that on average a doubling of blood lead was associated with a rise in blood pressure averaging 1 mm Hg systolic and 0.6 mm Hg diastolic. The older animal studies, however, failed to show a significant pressure increase with massive lead exposure. This review therefore attempts to determine whether the more recent animal studies are supportive of a positive association between lead exposure and blood pressure elevation. Of the 21 animal studies published since 1977, one was carried out in dogs, one in pigeons, and the remainder in various rat strains. In the articles in which all the lead doses had been higher than 1 ppm, the association between blood pressure and exposure was found to be positive in seven, inconsistent in three, absent in four, and negative in one. Of the six animal experiments that employed lead doses not exceeding 1 ppm, five reported a small pressor effect. One of these five positive low-dose studies, however, failed to show a dose-effect relationship when exposure was increased from 0.1 to 1 ppm. In conclusion, most, but not all animal studies published since 1977 found a positive association between blood pressure and lead exposure. However, publication bias may have inflated the number of positive studies appearing in the literature.(ABSTRACT TRUNCATED AT 250 WORDS)