Invited Commentary: Lead, Bones, Women, and Pregnancy—The Poison Within?

Howard Hu1,2, and Mauricio Hernandez-Avila1,3

1 Department of Environmental Health, Harvard School of Public Health, Boston, MA.
2 Channing Laboratory, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA.
3 Centro de Investigacion en Salud Poblacional, Instituto Nacional de Salud Publica, Cuernavaca, Morelos, Mexico.

Received for publication July 29, 2002; accepted for publication August 1, 2002.

Abbreviations: Abbreviation: NHANES, National Health and Nutrition Examination Survey.


    INTRODUCTION
 TOP
 INTRODUCTION
 REFERENCES
 
Twenty-five years ago, the exposure of the US general population to lead was relatively high. Combustion of leaded gasoline was at its peak, and lead was present as solder in food cans, as a component of residential paint, as a widespread contaminant in the workplace, and as an ingredient in many other consumer products. The price paid for such exposures was also very high. Some individuals experienced acute, symptomatic lead poisoning (blood lead levels generally greater than 40 µg/dl), and many others experienced significantly impaired function—manifesting as, for example, declines in intelligence quotient among children and increases in blood pressure and declines in renal function among adults.

Today, US environmental exposures are much lower. Active screening for lead poisoning and the removal of lead from gasoline and other consumer products has been largely responsible for a dramatic decline in overall lead exposure. For example, mean blood lead levels in the National Health and Nutrition Examination Surveys (NHANES), surveys of the US general population (1), decreased from 12.8 µg/dl (95 percent confidence interval: 12.3, 13.3) in 1976–1980 (NHANES II) to 2.8 µg/dl (95 percent confidence interval: 2.7, 3.0) in 1988–1991 (NHANES III)—arguably one of the greatest environmental health triumphs of governmental regulation in the United States in modern times.

Does that mean that lead toxicity is no longer a problem? Unfortunately, no. One reason is that elevated exposure persists in some segments of our society, in large part because of health and socioeconomic disparities. In the NHANES III data from 1988–1991 (2), mean blood lead levels were noted to remain substantially higher in some age-ethnicity strata, such as Black males aged 1–2 years (mean blood lead level = 6.3 µg/dl; 95 percent confidence interval: 5.6–7.2). The Centers for Disease Control and Prevention recently estimated that approximately 890,000 US children aged 1–5 years have blood lead levels exceeding the recommended limit (>10 µg/dl) from exposure to lead paint in old houses (3), and therapy for pediatric lead poisoning remains widespread enough to have prompted the National Institute of Environmental Health Sciences to fund a recent multicenter trial of its efficacy (4). Among adults, many workers remain occupationally exposed to lead, including over 1 million construction workers, for whom control of lead exposure using typical industrial hygiene methods has proven difficult (5).

However, another reason why lead toxicity remains a problem despite declines in ongoing exposure is the accumulation and persistence of lead in bone. Once ongoing exposures decline, lead levels in blood and all other soft tissues decline fairly rapidly; but this does not mean that lead has entirely left the body. Approximately 15 percent of all the lead that enters the body is sequestered in the skeleton, where it become incorporated into the hydroxyapatite mineral structure of bone and persists with a half-life of years to decades (68). As a result, over 95 percent of lead in a typical adult (more than 70 percent in children) can be found in bone (9, 10).

Does accumulated lead exposure, represented by bone lead levels, have long-term ramifications? Until recently, epidemiologic studies have lacked a noninvasive method for assessing bone stores of lead. Now, however, quick, safe, and noninvasive measurements of lead in bone can be made using techniques such as K x-ray fluorescence, utilized by Rothenberg et al. in the study described in this issue of the Journal (11). This technique has been successfully used in occupational studies of lead workers (for example, see Schwartz et al. (12) and Stewart et al. (13)) and community-based studies of elderly men and women (for example, see Hu et al. (14) and Korrick et al. (15)) to uncover relations between bone lead levels and risk of hypertension, kidney function, and cognitive functioning.

Rothenberg et al. (11) used K x-ray fluorescence to take direct measurements of bone lead levels in peripartum women. In addition, they employed advanced techniques to measure lead in maternal blood, blood pressure (they used an automated instrument, thereby enhancing precision and minimizing observer bias), and important covariates. Their analysis of the data was carefully done. Rothenberg et al. found that maternal bone lead levels in the calcaneus (a proxy anatomic site for assessing lead levels in trabecular bone) were associated with increased systolic and diastolic blood pressure as well as increased risk of third-trimester hypertension. These relations were fairly robust. Hypertension, in turn, is one of the most common complications of pregnancy, threatening fetal as well as maternal health. Mean maternal blood lead levels in Rothenberg et al.’s study were approximately 2 µg/dl, well below recommended maximum levels for adults and children, and they were not associated with either elevated blood pressure or an increased risk of hypertension.

Bone lead as a biologic marker of dose: potential mechanisms
What is the mechanism by which maternal bone lead levels may predict pregnancy-related outcomes such as increases in blood pressure and hypertension? One possibility is that maternal bone lead levels are a proxy for cumulative lead-induced damage to the kidneys and/or vascular system that, in turn, predisposes women to increased blood pressure during pregnancy. According to this potential mechanism, lead in maternal bone is not necessarily toxic per se but is a marker for long-term exposure and damage elsewhere in the body.

A more ominous possibility is that the mechanism involves the marked increases in mobilization of lead from maternal bone that have been demonstrated to occur during pregnancy. This phenomenon has been confirmed by elegant longitudinal observational studies of lead isotopic ratios in women conducted by Gulson et al. (16). What makes this possibility ominous is that marked increases in maternal bone lead mobilization almost surely result in increased lead exposure not only to maternal target organs but also to the fetus, since the placenta is not a meaningful barrier against the diffusion of lead from mother to fetus (17). Indeed, in the past few years, a US-Mexico international team has published a series of studies on the relation of maternal bone and blood lead levels to birth outcomes and infant development in which maternal bone lead levels were found to predict lower birth weight (18), less infant weight gain (from birth to 1 month (19)), lower head circumference and birth length (20), and, just recently, lower scores on the Bayley Scales of Mental Development at age 2 years (21). In the latter study, levels of lead in both maternal bone and umbilical cord blood had independent effects on mental development.

This mechanism is compelling, but it leaves a puzzle. One would expect that lead would be mobilized from bone into blood, making maternal blood lead levels the intermediate biologic marker of dose between bone and soft-tissue organ target sites. Why then did Rothenberg et al. and the US-Mexico team find that bone lead was better than maternal blood lead at predicting some adverse outcomes? One possibility is that such adverse outcomes are most dependent on lead that is mobilized from the maternal skeleton during the entire course of pregnancy, and that maternal bone lead levels are a better marker for integrating such a dose than a single measurement of maternal blood lead level. Another possibility is that lead mobilized from bone increases levels of lead in plasma—where it then crosses soft tissue membranes into target organs—in a way that is not reflected by measurable increases in whole blood lead levels. (Although lead in red blood cells, as opposed to plasma, comprises more than 99 percent of total lead in a blood specimen and therefore more than 99 percent of the variance in a blood lead measurement, lead in red blood cells is bound to proteins and is not readily bioavailable.) Some evidence, including early data from studies utilizing direct measurements of lead in plasma (22, 23), suggests that the ratio of lead in plasma to whole blood lead can vary by a factor of 2–3, with bone lead as a major determinant of plasma lead levels. Other evidence is less supportive of this notion (24).

We look forward to research that further addresses these issues. Regardless of the outcome, however, these research developments demonstrate how mechanisms of toxicity may be amenable to investigation through the use of increasingly more sophisticated biologic markers in epidemiologic studies.

Public health ramifications
The general implication of the work of both Rothenberg et al. and the US-Mexico team is that even if ongoing environmental lead exposure is no longer significant, lead toxicity can remain a problem as a long term sequela of the "poison within."

How generalizable are these findings? The Latino and African-American women studied by Rothenberg et al. in Los Angeles had mean levels of lead in tibia and calcaneus bones of 8 and 10.7 µg/g bone mineral, respectively (11). These levels are somewhat higher than the mean tibia and patella levels found by Hu et al. (25) in a postpartum study of mostly White middle- to upper-class women living in the Boston area (4.5 and 5.8 µg/g bone mineral, respectively; both the calcaneus and patella are trabecular bones). On the other hand, the mean tibia lead level observed was similar to that of women aged 27–30 years living near a smelter in Idaho (~8 µg/g bone mineral) (26) and approximately 30 percent lower than that of postpartum women living in Mexico City (27). Strict comparisons of these data are limited by the lack of a fully implemented intercalibration protocol within laboratories; however, the data suggest that the retained lead burdens of women studied by Rothenberg et al. are by no means unusual and that these investigators’ findings have potential implications for all women of reproductive age.

Additional research on bone lead levels and associated toxicity is warranted. Moreover, we believe it is not premature to conduct research on possible avenues for secondary prevention, that is, for reducing the mobilization of maternal bone lead during pregnancy or lactation. This is of particular importance given the results of the recent multicenter trial demonstrating that lead-associated declines in children’s mental development are not reversed by chelation (4). At term, the human fetus has gained approximately 30 g of calcium, mainly from maternal reserves. Calcium demand is met by increasing absorption in the maternal gastrointestinal tract and the resorption of maternal bone. An obvious potential intervention strategy that needs to be tested is nutritional: Can providing an exogenous source of calcium during pregnancy (i.e., calcium supplementation) suppress maternal bone resorption and thereby the mobilization of lead from maternal bone and resultant toxicity?

Experimental studies have shown that lead retention is higher among experimental animals fed on low-calcium, high-lead diets (2830). Controlled exposure studies among adults and children have documented that lead uptake decreases as dietary calcium increases (31, 32). In the study by Gulson et al. (16), two women who took dietary calcium supplements had the lowest mobilization of lead from bone to blood. In other studies of blood lead changes during pregnancy, women with higher calcium intakes were shown to have lower blood lead levels at the end of pregnancy, even at intakes that were well over the Recommended Dietary Allowance (3335). Finally, a recent randomized trial found that use of calcium supplements decreases maternal blood lead levels by approximately 15 percent in women during lactation—a period that, like pregnancy, involves increased resorption of maternal bone (36).

This kind of evidence is highly suggestive but not conclusive. Additional randomized trials designed to directly evaluate the potential effect of calcium supplementation during pregnancy are currently in progress or are being planned.

Conclusions
In conclusion, the findings of Rothenberg et al. and of other groups indicate that exposure to lead has far-reaching consequences. Long after ongoing exposures have declined, past lead exposure can affect maternal and fetal health, most likely through mobilization of bone lead stores that constitute a "poison within."

Clearly, this work gives additional urgency to worldwide efforts to reduce and prevent lead exposure in the workplace and the community. However, it also provides a rationale for ongoing efforts to test strategies (e.g., nutritional supplementation) for mitigating the effects of lead that has already accumulated in millions of young bodies. Given the emphasis traditionally given to primary prevention in environmental health, treatment and secondary prevention have rarely been the focus of research. Lead should be an exception.


    ACKNOWLEDGMENTS
 
This work was supported by grants R01ES07821, P42ES05947, and 2P30ES00002 from the National Institute of Environmental Health Sciences.


    NOTES
 
Reprint requests to Dr. Howard Hu, Channing Laboratory, 181 Longwood Avenue, Boston, MA 02115 (e-mail: hhu{at}hsph.harvard.edu). Back


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Related articles in Am. J. Epidemiol.:

Increases in Hypertension and Blood Pressure during Pregnancy with Increased Bone Lead Levels
Stephen J. Rothenberg, Vladislav Kondrashov, Mario Manalo, Jian Jiang, Rosa Cuellar, Mario Garcia, Blanca Reynoso, Sergio Reyes, Maria Diaz, and Andrew C. Todd
Am. J. Epidemiol. 2002 156: 1079-1087. [Abstract] [FREE Full Text]  




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