Low-level lead exposure and mortality in US adults is examined in a population-based cohort study, published in The Lancet Public Health.
A Before the Headlines analysis accompanied this roundup.
Prof Kevin McConway, Emeritus Professor of Applied Statistics at The Open University, said:
“The researchers make a very important point in their report – that it is more accurate to view this study as estimating how many deaths might have been prevented if historical exposures to lead had not occurred.
“In other words, they aren’t saying that current exposure to lead in the environment is the main thing here, as much of the exposure would have been in the past when regulation was much less strict than it is now. The lead author does state, however, that action needs to continue to reduce exposure.
“Lead tends to stay around in the body once it has entered it, so the blood lead levels of the people in this study will have been affected by exposure to lead throughout their lives: including exposure to lead in petrol before it was banned, and exposure from lead-based paint or lead drinking water pipes when those were more common than they are now.
“People starting their lives in the UK or USA now will, very likely, have lower blood lead levels when they grow up than did the people in this study, because several sources of lead pollution have been reduced. Assuming that the researchers’ statistical models are valid, numbers of cardiovascular deaths will decrease in the future because of those reductions in blood lead levels across the population.
“But, if lead has as strong a relationship to cardiovascular disease as these researchers describe, then changes in the level of lead in people’s blood in the past would have had major effects on numbers of deaths from cardiovascular diseases, particularly heart attacks.
“How much of the rise in deaths from heart disease over the past century might have been due to lead pollution, rather than all the other causes that have been put forward? Heart disease has been reducing in the UK and similar countries in recent decades; might this have more to do with reductions in lead levels than has been thought? I don’t think those questions can be answered in detail from this study alone, though the study may well lead to change in the way we understand trends in cardiovascular disease. Indeed, as the linked editorial by Landrigan points out, there may well be similar issues about several other pollutants.”
Prof Tim Chico, Professor of Cardiovascular Medicine and Honorary Consultant Cardiologist at the University of Sheffield, said:
“This paper shows a strong association between levels of lead in the blood and future risk of heart attack and dying. The relationship between lead levels and heart attack in this study was very strong; lead was potentially the cause of 37% of all deaths from heart attack in this study, which is about 10 times more than previous estimates.
“This is an “association study”; it can find a possible link between a factor like lead, and a disease such as heart attack, but it cannot prove that lead causes the disease directly. However, lead has a range of toxic effects on brain development and heart function and no known health benefits. The question is not therefore whether environmental pollutants such as lead cause premature death, but how many deaths, and this study suggests that lead, or factors that increase people’s exposure to lead, causes thousands more deaths every year than we previously recognised.
“In the last decades, we have made huge advances in understanding how to reduce an individual’s risk of heart disease; stopping smoking, regular physical activity, blood pressure and cholesterol lowering have all helped reduce the numbers of patients suffering a heart attack. It is likely that future advances will be less individual and more societal, such as redesigning transport systems and workplaces to encourage physical activity and global efforts to reduce exposure to pollutants such as lead and traffic fumes.”
Prof Sir Colin Berry, Emeritus Professor of Pathology, QMUL, has provided the following background on lead toxicity:
Lead is a cumulative general poison affecting many systems with varied clinical effects. In general prolonged exposure to high levels in water would be necessary before clinical manifestations of poisoning occur, however biochemical evidence of excessive lead exposure may be found without symptomatology.
Acute and chronic effects of lead poisoning are not clearly separable; acute episodes are often imposed on a background of illness related to chronic exposure. However, in the context of exposure to lead in drinking water it is not necessary to consider the effects of lead as an acute poison. Acute poisoning episodes are most frequently related to excessive inhalation of the metal in the form of dusts or vapor. As the respiratory tract allows 30–70% of inhaled lead to reach the circulation, blood levels may rise rapidly; the distinction of importance here is that oral ingestion generally results in only around 10% absorption.
Thus with chronic low level exposure, acute lead encephalopathy, where the patient presents with headache, vomiting, ataxia, convulsions, paralysis, stupor and coma is not to be expected. In terms of identifying a physical manifestation of over-exposure to lead the most likely indicator is anaemia. The US EPA has estimated the threshold blood lead level for a decrease in haemoglobin to occur to be 50 µg/dL. for occupationally exposed adults.
The way in which lead is handled by the body is important in both the development of symptomatology of lead poisoning and the detection of exposure. In terms of the total body burden in a chronically exposed adult, blood contains the rapidly exchangeable component of lead but accounts for only 2% of the total body burden (in blood, 95% is bound to the red cell membrane and the haemoglobin in the cell and 5% is in the plasma). Biochemically, the blood lead concentration reflects recent exposure; this component has a biological half-life (t1/2) of about 35 days. The remainder of the total body burden is distributed between an intermediate pool comprising skin and muscle, and a stable pool in dentine and the skeleton. This latter contains over 95% of the total body load and has a biological t1/2 of 20–30 years.
Effects on infants and children under 6 years of age.
The possible effects of chronic exposure to lead have been studied in a number of ways in infants and children. These have mainly been directed towards groups with relatively low levels of exposure (<40µg/dL. blood lead) and without symptoms. Unsurprisingly, the studies present problems common to many epidemiological investigations since they must attempt, with variable success, to account for potential confounding factors. These include difficulties in evaluating, in a consistent manner, the effects originating from nervous system damage, the temporal relationships of exposures to any demonstrable effects and a wide range of effects of other dietary factors, notably iron and calcium intake.
Studies of exposure may be Cross Sectional or Longitudinal. A Cross-Sectional study examines the relationship between a disease or other health related state and other variables of interest, as they exist in a defined population at a single point in time or over a short period of time – such as a month or year. Difficulties with cross-sectional studies include a non-response bias if participants who consent to take part in the study differ from those who do not. As data on each participant are recorded only once it is not possible to determine whether or not there is a temporal association between a risk factor and an outcome. Therefore, only an association, and not causation, can be inferred from a cross sectional study.
In a Longitudinal study data is gathered from the same subjects repeatedly over a period of time (in a longitudinal cohort study, the same individuals are observed over the study period). Longitudinal studies suffer from the problems of attrition with some subjects lost by death, refusal to continue to take part, or simple loss of contact. Members of the group may show conditioning where, over time, respondents can unknowingly change their qualitative responses as they become “trained “ in say, psychometric testing.
Data are available from Cross Sectional studies in the USA, the UK as a whole and Scotland, Germany and Greece. A series of studies, some repeating earlier observations, on about 800 children in the United Kingdom with blood lead levels between 4 and 32 μg/dL. failed to find any significant associations between lead and indices of intelligence and behaviour after socioeconomic and family characteristics were taken into account.
A number of longitudinal studies have been made, perhaps the most impressive being the Boston Lead Study where an apparent inverse relationship was demonstrated between fetal exposure, measured as lead levels in cord blood, and mental development at age 2. However, at 57 months, only the association between intelligence scores and blood lead 3 years previously, at age 2, remained significant after controlling for confounding variables.
A number of prospective studies have failed to show any consistent association between mental development and blood lead, either during the perinatal period or in early childhood. The appendix illustrates the difficulty of considering the effects on individuals rather than large cohorts. In looking at the data there appears to be a dose/effect relationship with an inverse relationship between IQ and lead levels but confidence intervals are wide for comparatively small changes.
Children and adolescents.
There are no data that identify a specific problem associated with this age group although central nervous system development is continuing. Problems of acute toxicity can be identified, for example Coulehan et al (1983) reported on a 6-year period when 23 Navajo adolescents were hospitalized 47 times for presumed lead intoxication secondary to gasoline sniffing. This (respiratory) route of ingestion not surprisingly meant that 65% of the patients first presented with toxic encephalopathy. Of total episodes, 31% involved asymptomatic lead overload; 31% involved tremor, ataxia, and other neurologic signs; and 38% involved encephalopathy with disorientation and hallucinations. There was one death.
This study provided useful data on the biochemistry of lead exposure in this age group. Free erythrocyte protoporphyrin levels were not consistently high, although blood lead levels were all elevated. Among 147 junior high school students, blood lead levels averaged 18 ± 6 µg/dL. with no values >40 µg/dL. Three of these “high-level” students had elevated zinc protoporphyrin levels and all three were anaemic. No correlation was found between levels of blood lead or zinc protoporphyrin and whether or not the youth reported sniffing gasoline.
Pregnancy and Lactation
Lead in the diet will affect calcium absorption if calcium levels in the diet are low in calcium. Two Cochrane systematic reviews investigated whether calcium supplementation on a daily basis during pregnancy improved maternal and infant outcomes but these findings are not related to lead status. If significant calcium mobilisation from the skeleton occurs during pregnancy with grossly deficient diets lead may also be mobilised into the blood component and reach the fetus.
The Communicable Disease Centre (CDC, USA), in acknowledging the benefits of breastfeeding considers that “adverse developmental effects of ≥5 μg/dL. in infant blood lead level was of greater concern than the risks of not breastfeeding”. They believe that mothers with blood lead levels <40 μg/dL. should be encouraged to breastfeed, but those with higher blood lead levels are encouraged to pump and discard their breast milk until their blood lead levels drop below 40 μg/dL.
These recommendations are clearly not appropriate in countries where infant mortality from infectious diseases is high.
Chronic disease and lead exposure
Both acute and chronic lead poisoning may cause a number of cardiovascular problems. In chronic exposure without symptomatology hypertension and the problems related to exacerbation of atherosclerosis have been linked, controversially, to chronic low-level lead exposure. Data from the second United States National Health and Nutrition Examination Survey (NHANES II) suggested a possible effect but detailed analysis of the data base by Gartside (1998) pointed out methodological problems with the former analysis by using forward stepwise regression. The results of this research for white male adults, white female adults, and black adults were contradictory and lacked consistency and reliability. In addition, the overall average association between blood lead level and blood pressure was so minute that he considered that the only rational conclusion is that no evidence for this association is to be found in the NHANES II data.
Renal disease has long been associated with lead poisoning; however, chronic nephropathy in adults and children has not been detected below blood lead levels of 40 μg/dL. Campbell et al (1977). Damage to the kidneys includes acute proximal tubular dysfunction and is characterized by the appearance of prominent inclusion bodies of a lead–protein complex in the proximal tubular epithelial cells at blood lead concentrations of 40–80 μg/dL. (Ritz, Mann and Wiecek 1988).
I know of no association between chronic low level lead exposure and immuno-compromisation.
The biochemical phenomena occurring during poisoning by lead and the pathogenesis of the poisoning process are described in an Appendix.
Bellinger D et al. Longitudinal analyses of prenatal and postnatal lead exposure and early cognitive development. New England Journal of Medicine, 1987, 316:1037-1043.
Campbell BC et al. Renal insufficiency associated with excessive lead exposure. British Medical Journal, 1977, 1:482-485
Coulehan JL, Hirsch W, Brillman B, Sanandria B, Welty TK , Colaiaco P, Koros A, Lober A. Gasoline Sniffing and Lead Toxicity in Navajo Adolescents. Pediatrics, 1983. 71: 113-117.
Gartside PS. The relationship of blood lead levels and blood pressure in NHANES II: additional calculations. Environmental Health Perspectives. 1988; 78: 31–34.
Harvey PG et al. Blood lead, behaviour, and intelligence test performance in preschool children. Science of the total environment 1984, 40:45-60.
Landsdown RG Yule W, Urbanowicz M-A et al. Blood-lead levels, behaviour, and intelligence: a population study. Lancet, 1974 : 538-541.
Lansdown RG et al. The relationship between blood-lead concentrations, intelligence, attainment and behaviour in a school population: the second London study. International archives of Occupational and Environmental health, 1986, 57:225-235.
Ritz E, Mann J, Wiecek A. Does lead play a role in the development of renal insufficiency? Contributions to Nephrology, 1988, 64:43-48.
6 (ii) To explain the internationally accepted or recognised guidelines and/or parameters (and their rationales) particularly those adopted by WHO, on the content of lead in (a) tap water and (b) blood in human beings.
Legislation relating to lead poisoning was initially mainly directed to industrial exposure and for example, the UK Control of Lead at Work Regulations 2002 (CLAW) reflects this. Later concerns about lead derivatives in petrol, mainly anti premature ignition factors such as tetraethyl lead, an organo-lead compound with the formula (CH3CH2)4Pb lead to the phasing out of this type of compound in the mid-1970s, mainly because of its cumulative neurotoxicity and but also because of its damaging effect on catalytic converters. Air and soil pollution were also considered to be important.
WHO Guidelines for Drinking-water Quality (GDWQ) have undergone regular revision since 1984-5 most recently in 2011 and advice on lead from the Joint FAO/WHO Expert Committee on Food Additives (JECFA) provides information on the rationale behind current thinking. A JECFA committee considered the neurodevelopmental effects of lead on children to be critical, accepting the extrapolation from meta-analyses that 0.6µg/kg/bw/day resulted in an estimated decrease of 1 IQ point (5th to 95th percentiles 0.2–7.2 μg/kg bw/day). Their conclusions on blood pressure are less convincing in view of the re-analysis of the NHANES II data (see above) but the general conclusion that a permissible tolerable weekly intake (PTWI) for lead could not be established and should be withdrawn is reasonable as analyses do not indicate a threshold for the key effects of lead.
The Committee stressed that these estimates are based on dietary exposure (mainly food) and that other sources of exposure to lead also need to be considered.
In 2010, the United States of America Centres for Disease Control and Prevention (CDC) charged its Advisory Committee for Childhood Lead Poisoning Prevention (ACCLPP) to form a workgroup to evaluate new approaches, terminology, and strategies for defining elevated blood-lead levels (BLLs) among children. The main issue was to interpret changes in childhood BLLs and trends in childhood BLLs over time in order to give advice about regulation (other issues, such as the methodology of measurement of lead in the body were also considered).
The recommendations of the group included:-
Elimination of the use of the term “blood lead level of concern” based on what was considered to be compelling evidence that low BLLs are associated with IQ deficits, attention-related behaviours, and poor academic achievement. The absence of an identified BLL without deleterious effects, combined with the evidence that these effects appeared to be irreversible, emphasised the critical importance of primary prevention.
ACCLPP also recommended using a reference value based on the 97.5th percentile of the BLL distribution among children 1–5 years old in the United States (currently 5 μg/dL.) to identify children with elevated BLLs (they would use data generated by the National Health and Nutrition Examination Survey (NHANES). Approximately 450,000 children in the United States have BLLs higher than this reference value.
CDC Updates Guidelines for Children’s Lead Exposure. Betts, Kellyn S. Environmental Health Perspectives120.7 (Jul 2012): a268.
The Pathogenesis of Lead Poisoning
Clinical adult lead poisoning is usually considered to be established at a blood lead level ≥40 μg/dL., where, as indicated above, symptoms may occur in adults. They are more usually manifest with levels exceeding 50-60 μg/dL. A commonly used indicator of poisoning is anaemia, which in lead poisoning is typically hypochromic and microcytic with basophilic stippling of red cells. It should be emphasised that it is a late complication and generally appears only when blood lead concentrations exceed 2.40 µmol l−1 (50 µg 100 ml).
Red cells are continually developing in the bone marrow and circulate for about 100–120 days before they are destroyed. They have no nucleus and are essentially transporters of a protein complex, haemoglobin that binds and releases oxygen readily. This property depends on a loose binding with one of the six valences of the iron atom and is readily reversible. The oxygen is thus carried as molecular oxygen to the tissue where it is released into the tissue fluids.
The properties of haemoglobin as a transporter depend on this bonding. The production of the haeme in the molecule is a multi-step process that requires eight different enzymes. Delta-aminolevulinate dehydratase (ALAD) is responsible for the second step in this process, which combines two molecules of delta-aminolevulinic acid (the product of the first step) to form a compound called porphobilinogen. In subsequent steps, four molecules of porphobilinogen are combined and then modified to produce haeme.
Lead decreases haeme biosynthesis by inhibiting d-aminolevulinic acid dehydratase (ALAD) and decrease in the activity of this enzyme results in an increase of the substrate, erythrocyte protoporphyrin (EP) in the red blood cells where it is found in the form of ZPP – bound to zinc rather than to iron. Ferrochelatase, which catalyzes the insertion of iron into protoporphyrin IX, is also inhibited by lead.
Protoporphyrin elevation lags behind the rise in blood lead and after the cessation of exposure, takes longer to resolve. In general, free erythrocyte protoporphyrin (also measured as zinc protoporphyrin) reflects the last 6-8 weeks of exposures and is normally less than 35 μg/dL.
Inhibition of ALAD activity occurs over a wide range of blood lead levels beginning at <10 μg/dL. The anaemia induced by lead is the result of inhibition of both haeme synthesis as described above and shortening of erythrocyte lifespan. However, lead also can induce inappropriate production of the hormone erythropoietin leading to inadequate maturation of red cell progenitors so that there is a shortage of new red cells.
Froom et al (1998) concluded that ZPP may be a better measure of chronic lead exposure because of its longer half-life (63 days in their study), whereas PbB (blood lead) could be a superior indicator of short exposure. In chronic exposure, PbB peaks at 3–6 months, whereas ZPP peaks at 6–9 months. After the elimination of exposure, ZPP concentrations remain above healthy reference values for up to 2 years, whereas PbB concentrations decrease more rapidly. They pointed out the lower specificity of ZPP, which increases not only in lead poisoning but also in iron deficiency and in anemia of chronic disease.
The biochemistry of the poisoning process
Lead has a high affinity for sulfhydryl groups and inhibits sulphydryl dependent enzymes including 5-aminolaevulinic acid dehydratase (ALAD) and ferrochelatase, which are essential for the synthesis of haem. Divalent lead acts in a manner similar to calcium and competitively inhibits the actions of calcium in important areas such as mitochondrial oxidative phosphorylation and the intracellular messenger system normally regulated by calcium, thus affecting endocrine and neuronal function. Although lead can affect the genetic transcription of DNA by interaction with nucleic acid binding proteins is not convincing evidence that lead is a human carcinogen.
Inhibition by lead of cytosolic ALAD prevents the formation of porphobilinogen and accumulation of the precursor 5-amino-laevulinic acid (ALA) in the plasma may play a significant role in the pathogenesis of lead poisoning by triggering an oxidative stress response, as in acute intermittent porphyria. In massive exposures it might be assumed that many thiol containing anti-oxidants and enzymes would be inhibited including superoxide dismutase, catalases, glutathione peroxidase, glucose-6-phosphate dehydrogenase which would increase oxidative stress; nitric oxide synthetase inhibition by interference with its Ca++ dependent action is a possible explanation of CNS effects.
Inhibition of mitochondrial ferrochelatase prevents the incorporation of ferrous iron into protoporphyrin IX. Consequently free protoporphyrin IX accumulates and forms a metal chelate with zinc, which remains in the erythrocyte for its life-time. Zinc protoporphyrin (ZPP) is thus an indicator of exposure to lead over the prior 3 months.
* ‘Low-level lead exposure and mortality in US adults: a population-based cohort study’ by Bruce P Lanphear et al. published in The Lancet Public Health on Monday 12th March 2018.
Prof Kevin McConway: “I was lead author of a chapter for the Chief Medical Officer’s recently published report on health impacts of pollution. I am a member of the Science Media Centre’s Advisory Committee.”
Prof Tim Chico: “No conflicts.”
None others received.