The effect of lead on thyroid function in children

ENVIRONMENTALRESEARCH49, 190--196 (1989)

The Effect of Lead on Thyroid Function in Children MICHAEL SIEGEL,~ BRIAN F O R S Y T H , t L E W I S SIEGEL,* AND MARK R . CULLEN~: *Department of Laboratory Medicine, Stamford Hospital, Stamford, Connecticut, and ?Department of Pediatrics and $Occupational Medicine Program, Yale University School of Medicine, 333 Cedar St. New Haven, Connecticut 06510 Received December 22, 1988 Exposure to inorganic lead has been associated with impaired uptake of iodine by the thyroid as well as depressed estimated free thyroxine levels in occupationally exposed adults. Consideration of the serious consequences of impaired thyroid function in young children prompted investigation of the effects of lead on thyroid function in children. Blood lead determinations and thyroid function tests were performed on 68 children examined at a hospital outpatient pediatric clinic. Serum thyroxine (T4) and free thyroxine (FT4) levels were within the normal range for all patients. No statistically significant relationship was found between lead levels and T4 or FT4 levels. We conclude that lead is unlikely to have a clinically significant effect on thyroid function in children exposed in inner cities at prevailing levels. © 1989AcademicPress, Inc.

INTRODUCTION Despite increased knowledge of the effects of childhood lead exposure, improved diagnostic techniques, and widespread lead screening programs, childhood lead poisoning continues to be a major public health problem. The second National Health and Nutrition Examination Survey (NHANES II, 1976-1980) indicated that among children 6 months to 5 years of age, the prevalence of elevated blood lead levels was 4%; however, 12.2% of black children had elevated levels (Mahaffey et al., 1982). The NHANES data show that lead exposure is still a significant public health concern, especially for children who are black, poor, or living in the inner city. Research on the biological effects of lead exposure in children has focused on hematological effects (inhibition of heme and globin synthesis), central nervous system effects (encephalopathy, subtle neuropsychological deficits), peripheral nerve dysfunction (slowed conduction velocity, electrophysiological deficits), and renal effects (acute renal injury, aminoaciduria, glycosuria) (Farfel, 1985). In addition, it has been suggested that low-level lead exposure may impair growth in children (Schwartz et al., 1986; Mooty et al., 1975; Johnson and Tenuta, 1979). More recently, several endocrine manifestations of lead poisoning in children have been identified, including impaired synthesis of 1,25-dihydroxyvitamin D (Mahaffey et al., 1982; Rosen et al., 1980), impaired hepatic metabolism of cortisol (Saenger et al., 1984), and increased somatomedin activity (Rohn et al., 1982). A recent study has demonstrated depression of TSH release in severely lead-poisoned children (Huseman et al., 1987). However, the significance of these findings in children with lower levels of exposure and their relationship to observed growth and mental retardation are uncertain. 190 0013-9351/89 $3.00 Copyright © 1989by AcademicPress, Inc.

All fights of reproduction in any form reservexL

LEAD AND THYROID FUNCTION IN CHILDREN

191

A wide range of possible endocrine manifestations has been recognized in leadpoisoned adults. These include gonadal and reproductive effects (Rohn et al., 1982), decreased adrenal and pituitary function (Sandstead et al., 1970), and depressed thyroid function (Slingerland, 1955; Sandstead, 1967; Sandstead et al., 1969; Robins et al., 1983; Tuppurainen et al., 1988). In particular, the effects of lead on the thyroid have been repeatedly demonstrated. As early as 1955, lead was shown to inhibit the in vitro uptake of iodine by the thyroid gland (Slingerland, 1955). Later, this result was confirmed by Sandstead et al. in an in vivo study of rats (1967), as well as in 24 lead-poisoned human patients (Sandstead, 1969). In 1983, Robins, Cullen, and co-workers found depressed thyroid indices in 12 foundry workers referred because of elevated blood lead levels. Further investigation of all 47 male workers at the foundry revealed a statistically significant negative association between estimated free thyroxine and blood lead levels, suggesting that lead may impair thyroid function in adults, at least in those chronically exposed. A more recent study (Tuppurainen, 1988) of 176 males occupationally exposed to lead found a weak but significant negative association between duration of lead exposure and free thyroxine levels. Duration of exposure was found to be strongly associated with thyroxine levels in those workers with the most intense exposure. The purpose of this study was to determine whether or not the observed negative association between blood lead levels and thyroid indices in adults occurs in children with lead exposures typically found in urban environments. The importance of such a relationship in children would be twofold. First, finding impairment of thyroid function in lead-poisoned children could have important clinical significance, given the grave consequences of even transient hypothyroidism in the very young. Second, finding lead-induced hypothyroidism in children could provide a possible mechanism for the established effects of lead on growth and mental performance in children.

METHODS Design. The Pediatrics division of the Primary Care Center at Yale-New Haven Hospital is an outpatient clinic serving a chiefly lower-class, black, and Hispanic population in New Haven. The clinic's Lead Screening Program consists of two parts. First, children considered at risk for lead poisoning are screened during routine visits for zinc protoporphyrin (ZPP) by finger-stick. If the ZPP is elevated (>30 ~g/dl), a venous blood sample is taken for determination of blood lead concentration. Second, children known to have had elevated blood lead levels in the past are subjected to venipuncture for lead determination without prior ZPP screening. In these cases, ZPP is determined from the venous blood sample. During the summer of 1987, 72 children from both of these groups were entered into our study. Because one parent refused consent to participate, and an adequate blood sample could not be obtained from three children, the total sample size was 68. For each subject, venous blood was obtained for lead determination and for indices of thyroid function (total thyroxine (T4) and T4 uptake). In addition, the following data, obtained from clinic charts and from a parental question-

192

SIEGEL ET AL.

naire, were available for each child: age, sex, race, socioeconomic status (method of payment), and hemoglobin. A protocol, including procedures to obtain oral consent from a parent of each subject, was approved by the Yale University School of Medicine's Human Investigation Committee before beginning the study. Study population. The study group consisted of 36 males and 32 females with an age-range of 11 months to 7 years, and a median age of 25 months. Forty-eight (70%) were black, 19 (28%) Hispanic, and 1 white. In all but six of the cases, visits were being paid for by Medicaid or state aid. One parent had private insurance, and the remaining five were paying for the visit themselves. Laboratory analysis. Samples for zinc protoporphyrin analysis were obtained by finger-stick. ZPP was measured in the clinic laboratory on a hematofluoremeter. Whole blood lead determination was performed by the Yale--New Haven Hospital Clinical Laboratories, using flameless atomic absorption spectrophotometry; the laboratory is certified by the Center for Disease Control, Atlanta, for lead analysis. All thyroid function tests were performed by the Stamford Hospital Clinical Laboratories. Blood samples were collected in a red-top vacutainer tube with silicone separator and were immediately centrifuged for 10 rain. Samples were refrigerated and transported weekly to Stamford Hospital in a cooler. Total thyroxine and T4 uptake (T4U) were measured by fluorescence polarization (Abbott TDX). Free thyroxine concentration was determined by the following calculation: FT4 = (T4/T4U) x 0.15 +0.03T4. The determination of FT4 by this formula correlates with free thyroxine measured by polyacrylamide gel filtration, which in turn closely correlates with FT4 measured by equilibrium dialysis (McDonald et al., 1978). Statistical analysis. Data were analyzed by standard linear regression analysis using the SAS statistical package. RESULTS The distribution of blood lead levels among the 68 children in the study is shown in Table 1. Lead levels ranged from 2.0 to 77 ~g/dl, with a mean value of 25 i~g/dl. Thirty children (44%) had elevated lead levels (>24 ~g/dl) as defined by the Center for Disease Control in 1985 (CDC, 1985). Ten patients required a calciumEDTA provocation test and/or outpatient chelation therapy; two were admitted to Yale-New Haven Hospital for inpatient chelation therapy. (Children with lead TABLE 1 DISTRIBUTION OF BLOOD LEAD LEVELS Blood lead level (p~g/dl)

Number of cases

<25 25-39 40-59 ~>60

38 18 8 4

LEAD AND THYROID FUNCTION IN CHILDREN

193

levels between 40 and 55 ixg/dl are given a calcium-EDTA provocation test to assess the need for outpatient chelation therapy.) Total thyroxine levels ranged from 5.1 to 13.1 lxgJdl with a mean of 9.5 txg/dl. FT4 levels ranged from 0.9 to 2.0 ng/dl, with a mean of 1.6 ng/dl. Only one patient was identified with a FT4 value below 1.0 ng/dl (normal range 0.9-2.1). This child had a T4 of 5.1 txg/dl, an FT4 of 0.9 ng/dl and a lead level of 45 lzg/dl. The observed relationship between FT4 and Pb values is shown in scatterplot form in Fig. 1. A standard linear regression of FT4 on Pb levels showed no significant effect of lead on the FT4 level (P = 0.02; P = 0.28). The regression showed a 95% confidence interval for lead effect equal to a 0.24- +0.32-ng/dl increase in FT4 per 100 lzg/dl of blood lead. This result was compared to that of Robins et al. (1983), who found a lead effect in adult subjects equal to a 0.42- + 0.40-ng/dl decrease in FT4 per 100 Ixg/dl of blood lead. The 95% confidence interval around the regression coefficient for lead in this study (-0.0008 to + 0.0056) does not include the regression coefficient for lead in the Robins study ( - 0.0042).

Results obtained using T4 as the dependent variable and ZPP as the independent variable were similar (Table 2). This is not surprising considering the strong correlation between T4 and FT4 (Pearson r = 0.81) and between Pb and ZPP (Pearson r = 0.63) in our data. The relationship between duration of exposure and free thyroxine level was examined using age as an indicator of duration of exposure. Our use of age as an indicator of duration of exposure is based on the assumption that lead exposure is relatively constant during early childhood in our inner city population. There was no significant association between age and FT4 for the population as a whole (Pearson r = - 0.09; P = 0.46). However, for severely lead-poisoned children (Pb I> 40 ~g/dl), there was a negative association between age and FT4 which approached significance (N = 12; Pearson r = -0.56; P = 0.06). Standard linear regression of FT4 on age in these 12 children showed an effect equal to a 0.19-0.18-ng/dl decrease in FT4 per year of age (r2 = 0.32; P = 0.06).

2.2 2.6 oo

ooj

1.8 o j ~ /.6 E

~ U_

•

go

•

oo

---.-

•

•

i

ooo

:

..

1.4 go

~

1.2

•

•

•

•

1.0

080

1'0

2'0

3'0

4'o

io

6'0

7'o

8'o

Pb, pg/dl of Whole BLood FIG. 1. Free thyroxine (FT4) level as a function of blood lead (Pb) level in the 68 study subjects. Regression line and confidence intervals (-+2 SD) are shown.

194

SIEGEL E T A L .

TABLE 2 REGRESSION OF THYROID FUNCTION ON INDICATORS OF LEAD ABSORPTION (BLOOD LEAD AND ZINC PROTOPORPHYRIN) Model (SE in parentheses) FT4 FT4 T4 T4

= = = =

1.55(0.05) 1.60(0.04) 8.96(0.39) 9.41(0.31)

+ + + +

0.0024(.0016)Pb 0.0003(.0003)ZPP 0.0210(.0127)Pb 0.0028(.0025)ZPP

R2

P

0.03 0.02 0.04 0.02

0.13 0.31 0.10 0.26

DISCUSSION In this paper, we present data suggesting that there is no significant relationship between blood lead levels and thyroid function in lead-exposed children. Previous research on the effect of lead on the thyroid has demonstrated a lead-induced inhibition of iodine uptake by the thyroid in vitro (Slingerland, 1955), in rats (Sandstead, 1967), as well as in adult patients (Sandstead et al., 1969). Robins and co-workers reported a substantial negative relationship between blood lead levels and thyroid function in lead-exposed workers (1983). Several factors might explain the discrepancy between these results and the findings of Robins et al. First, age differences between the two clinical populations could account for the difference in observed relationships between lead exposure and thyroid function. Robins and co-workers were studying adults aged 20 to 64; the subjects in this study were young children with a median age of 25 months. It is possible that children are less susceptible to the toxic effects of lead on the thyroid. This explanation, however, is not in agreement with the observation that children are generally more sensitive than adults to environmental toxins, especially to lead in terms of its neurological effects. Second, lower levels of exposure to lead among the children in this study compared to the lead-exposed foundry workers could account for our failure to find a significant effect of lead on thyroid function. The mean blood lead level in the black foundry workers was 51.9 p,g/dl, compared to a mean of 25 ~g/dl in the children in this study. In addition, several of the foundry workers had Pb levels greater than 100 ~g/dl, including a maximum level as high as 117 txg/dl. Nevertheless, our failure to find any evidence of hypothyroidism in four children with lead levels greater than or equal to 60 ixg/dl (and as high as 77 ixg/dl) suggests that differences in the magnitude of blood lead levels between the two populations do not fully explain our observations. A third possibility is that differences in duration of exposure explain why a significant effect of lead on the thyroid was demonstrated in lead-exposed workers, but not in lead-poisoned children. All but four of the 47 foundry workers had been employed longer than 9 months, and the mean duration of employment was 5.8 years. Even if all of the children in this study had been exposed to lead from the time of birth, the mean duration of exposure would have been only 2.8 years. Moreover, it is possible that duration of exposure, rather than blood lead level is most strongly associated with FT4 levels. Tuppurainen et al. (1988) failed to find a significant relationship between blood lead levels and thyroid indices, but

LEAD AND THYROID FUNCTION IN CHILDREN

195

did find a significant negative association between duration of occupational lead exposure and FT4 level, particularly in workers with the greatest exposure. We found a similar relationship in the severely lead-poisoned children in this study, using age as an indicator of duration of exposure. The effect on FT4 of each year of age (exposure) in this study was somewhat greater than in the Tuppurainen study (0.19- -0.18-ng/dl decrease in FT4 per year of age vs 0.03G- -0.016-ng/dl decrease in FT4 per year of exposure). Although our results are based on only 12 severely lead-poisoned children, the magnitude of the effect of duration of exposure (age) on FT4 in our data suggests that further study of the effect of duration of exposure on thyroid function in children may be quite important. Finally, it is possible that T4 and FT4 levels are not sensitive enough measures to detect impairment of thyroid function. Huseman et al. (1987), in a study of two severely lead-poisoned children, found that while T4 and FT4 levels were normal, there was a blunted TSH response to TRH stimulation in these children. It may be that FT4 is not a sensitive enough measure to detect impairment of thyroid function at the level of the pituitary. The significance of the findings reported in this study is threefold. First, our results suggest the need for study of the effect of duration of exposure on thyroid function in children. Second, the results suggest that the assessment of thyroid function in children with lead toxicity should include measurement of TSH as well as T4 and FT4 levels. Third, our observations make it seem unlikely that retarded growth and mental impairment in lead-poisoned children is due in part to leadinduced hypothyroidism. Finally, while this study was not designed to measure the extent of childhood lead poisoning in New Haven, our identification of 30 children with elevated lead levels (12 requiring a provocation test or chelation therapy) in a 3-month period cannot go unnoticed. It should serve as a reminder that childhood lead poisoning is still a significant public health problem, especially in children living in the inner city. ACKNOWLEDGMENTS We thank Lucille Tomasso, Regina Malatesta, Della Smith, and Marie Robinson at the Yale Primary Care Center, and Kay Delaney at the Stamford Hospital Laboratory for their help in making this study possible.

REFERENCES CDC (1985). Preventing poisoning in young children: A statement by the Centers for Disease Control, Atlanta, Georgia. Department of Health and Human Services. Farfel, M. R. (1985). Reducing lead exposure in children. Annu. Rev. Public Health 6, 333-360. Huseman, C. A., Moriarty, C. M., Angle, C. R. (1987). Childhood lead toxicity and impaired release of thyrotropin-stimulating hormone. Environ. Res. 42, 524-533. Johnson, N. E., Tenuta K. (1979). Diets and lead blood levels of children who practice pica. Environ. Res. 18, 36%376. Mahaffey, K. R., Annest, J. L., Roberts, J., Murphy, R. S. (1982). National estimates of blood lead levels: United States, 1976--1980.N. Engl. J. Med. 307, 573-579. Mahaffey, K. R., Rosen, J. F., Chesney, R. W., Peeler, J. T., Smith, C. M., DeLuca, H. F. (1982). Association between age, blood lead concentration, and serum 1,25-dihydroxycholecalciferol levels in children. Arner. J. Clin. Nutr. 35, 1327-1331.

196

SIEGEL ET AL.

McDonald, L. J., Robin, N. 1., Siegel, L. (1978). Free thyroxine in serum as estimated by polyacrylamide gel f'titration. Clin. Chem. 24, 652-656. Mooty, J., Ferand, D. F., Jr., Harris, P. (1975). Relationship of diet to lead poisoning in children. Pediatrics 55, 636--639. Robins, J. M., Cullen, M. R., Connors, B. B., Kayne, R. D. (1983). Depressed thyroid indexes associated with occupational exposure to inorganic lead. Arch. Intern. Med. 143, 220-224. Rohn, R. D., Hill, J. R., Shelton, J. E. (1982). Somatomedin activity before and after chelation therapy in lead-intoxicated children. Arch. Environ. Health 37, 369--373. Rosen, J. F., Chesney, R. W., Hamstra, A., DeLuca, H. F., Mahaffey, K. R. (1980). Reduction in i,25-dihydroxyvitamin D in children with increased lead absorption. N. Engl. J. Med. 302, 1128-1131. Saenger, P., Markowitz, M. E., Rosen, J. F. (1984). Depressed excretion of 6B-hydroxycortisol in lead-toxic children. J. Clin. Endocrinol. Metab. 58, 363-367. Sandstead, H. H. (1967). Effect of chronic lead intoxication on in vivo 1-131 uptake by the rat thyroid. Proc. Soc. Exp. Biol. Med. 124, 18. Sandstead, H. H., Orth, D. N., Abe, K., Stiel, J. (1970). Lead intoxication: Effect on pituitary and adrenal function in man. Clin. Res. 18, 76. Sandstead, H. H., Stant, E. G., Brill, A. B., et al. (1969). Lead intoxication and the thyroid. Arch. Intern. Med. 123,632-635. Schwartz, J., Angle, C., Pitcher, H. (1986). Relationship between childhood blood lead levels and stature. Pediatrics 77, 281-288. Slingerland, D. W. (1955). The influence of various factors on the uptake of iodine by the thyroid. J. Clin. Endocrinol. 15, 131. Tuppurainen, M., Wagar, G., Kurppa, K., Sakari, W., et al. (1988). Thyroid function as assessed by routine laboratory tests of workers with long-term lead exposure. Scand. J. Work Environ. Health 14, 175-180.