Health Effects of Lead in Children

Transcription

1 Health Effects of Lead in Children Thomas D Matte, MD, MPH, National Center for Environmental Health, US Centers for Disease Control and Prevention, USA

2 General issues concerning evidence Epidemiologic studies identify subtle effects not evident as abnormal clinical findings Exposure measures Low blood lead is relative since exposure ubiquitous Relevant timing of exposure varies by effect Most important findings have been replicated in diverse populations and study designs Animal data have demonstrated all major health effects seen in humans and validate blood lead as exposure metric

3 Mechanisms of lead toxicity

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5 Lead effects fundamental biochemical processes Bind to proteins, especially sulfhydryl groups Interfere with calcium-dependent processes Activates protein kinase C greater affinity for Pb than calcium Cell growth and differentiation Interference with blood brain barrier Regulation of long-term potentiation, involved in memory Dose-response relation with no evident threshold Activates calmodulin Synaptic transmission Interferes with heme biosynthesis

6 Derived from EPA Air Quality Criteria for Lead, 1986

7 Impact of Reduction of Heme Body Pool by Lead Anemia reduced oxygen transport Impaired neural cellular energetics Reduced 1,25 (OH) 2 Vitamin D disturbed calcium metabolism Impaired hepatic metabolism of endogenous agonists and xenobiotics Derived from EPA Air Quality Criteria for Lead, 1986

8 Fatal Pediatric Pb Poisoning 3/29/00-30 month old girl seen in ED w low-grade fever, vomiting x1 day Microcytic anemia (hgb 7.6 g/dl), occasional basophilic stippling Treated for presumed strep throat 4/17/00 Admitted with worsening vomiting 4/19/00 suddenly unresponsive, apneic, hypotensive CT diffuse cerebral edema, dilated ventricles BLL 391 µg/dl, EP 541 µg/dl 4/21/00 Remains unresponsive despite chelation - pronounced brain dead

9 Acute lead poisoning Early symptoms blood lead levels > ~ 50 µg/dl - may include anorexia, irritability, decreased play, disturbed sleep pattern Lead colic blood lead levels > ~ 60 µg/dl - sporadic vomiting and abdominal pain, constipation Symptoms may wax and wane or there may be no symptoms prior to sudden onset of encephalopathy - blood lead levels usually > 100 g/dl Persistent vomiting, ataxia, fluctuating state of consciousness, coma, seizures

10 Acute Lead Poisoning Signs which may be present but are not reliable: Gingival lead lines Radiographic growth arrest lines if present supportive evidence of chronic exposure Basophilic stippling of red cells

11 Lead poisoning should be considered in differential diagnosis of unexplained illness including: Anemia Seizures Lethargy Abdominal pain Must obtain blood lead level

12 Chronic Lead Toxicity

13 Source: National Academy of Sciences, 1993

14 Source: Landrigan et al, Pediatrics, 1976

15 Neurologic Impaired cognitive development At low levels, not clinically evident At population level, important, economic implications No threshold has been identified Appears to persist Behavior decreased attentiveness, increased impulsiveness, Increased hearing threshold Impaired nerve conduction

16 Hematologic ALAD activity inversely related to blood lead down to low levels (~3 g/dl) Increased EP or ZPP > ~ 30 µg/dl Anemia > ~ 50 µg/dl

17 Acute Renal Effects Acute nephropathy in lead poisoned children Proximal tubular dysfunction Aminoaciduria, glucosuria, phosphaturia?reversible in one study persistent glucosuria and aminoaciduria 8-13 years after treatment for severe lead poisoning PbB at time of follow-up 18.5 µg/dl

18 Chronic Renal Effects Effects of prolonged high exposure Reduced gfr, azotemia, interstitial fibrosis Nonspecific findings Also implicated in gout and hypertension Low-level exposure Inverse relation of BLL and creatinine clearance at lower levels of exposure Excretion of tubular proteins more sensitive than renal function tests but non-specific for lead

19 Chronic Renal Effects (cont)?chronic lead nephropathy in children Follow-up study of lead poisoned children in Queensland Excess of deaths from nephritis & hypertension often with hyperuricemia and gout Direct relation of blood lead to n-acetyl beta-dglucosaminidase (NAG)-urine and retinol binding protein in two studies Long term follow-up studies inconsistent in US cohorts

20 Cardiovascular Effects Direct relation of blood lead to blood pressure in adults down to levels at least as low as 5-10 µg/dl some inconsistency of specific pattern (systolic vs diastolic) Long-term follow-up of lead poisoned children supports increased risk of hypertension and CVD Rat studies are consistent with human data

21 Source: Loghman-Adham, M. Environmental Health Perspectives 1997;105

22 Growth In cross-sectional and longitudinal studies, weight of evidence supports small effect on stature e.g. In Mexican-American children 5-12 years of age in HHANES, children with PbB above median (~10 g/dl) ~ 1.2 cm shorter than children below median (Frisancho et al, Am J Clin Nutr 1991)

23 Summary Evidence of lead toxicity at blood lead levels still common worldwide, especially developmental neurotoxicity, is extensive in humans and supported by animal studies. Severe clinical lead poisoning can present with subtle non-specific symptoms or no symptoms prior to rapid deterioration

24 Summary (cont) Because of the log-normal distribution of blood lead, low-level, many more children are harmed by sub-clinical effects of lead than by clinical lead poisoning. Available evidence indicates that the only effective interventions for low-level lead toxicity are those that control lead exposure.