This study provides epidemiological evidence for an association between exposure to environmental pollutants and a reduction of antibody production after routine childhood immunizations. The children examined came from population-based birth cohorts and were in good health. As anticipated [9
], the antibody concentrations varied substantially, while known or suspected risk factors had little impact in comparison with PCB exposure. Although statistically significant associations with PCB exposure were demonstrated, the CIs were wide (). Results from the two different birth cohorts examined at ages 18 mo and 7.5 y showed some differences, but the tendencies seen with the tetanus and diphtheria toxoid antibody results are in overall agreement. Although the Faroese population has a substantially increased PCB exposure [23
], the results of the present study suggest that possible adverse influences on the immune function may well occur also at lower exposure ranges prevalent worldwide.
The conclusions from this study must consider the uncertainty associated with the incomplete information on PCB exposure, which included analyses of body fluid samples widely separated in time. While the PCB body burden at birth reflects the mother's exposure, breast-feeding may transfer substantial amounts of the mother's accumulated PCBs via the milk fat [24
]. Thus, the postnatal PCB body burden increases with the duration of the breast-feeding period [25
]. The serum analyses available therefore present a crude picture of the exposure profile, and such imprecision is likely to cause an underestimation of the true effect of the exposure [26
The Faroese population is also exposed to other seafood contaminants [12
], and effects of p,p
′-DDE and PCB could not be separated due to their close association; other potential confounders appeared to affect the results to a minimal degree. Regarding potentially causative PCB congeners, the associations may be affected by differences in their persistence. Thus, the persistent non-dioxin-like di-ortho
PCB congeners constitute the majority of the PCB in the samples analyzed, and their concentrations will therefore tend to be fairly robust. However, the immunotoxic effects could be due to past exposures to congeners (e.g., mono-ortho
PCBs or other dioxin-like compounds), which may no longer be present in serum in detectable concentrations, due to their shorter half-life. In this case, the more persistent PCBs may act as indicators of other congeners that caused the toxic effects. The present study cannot resolve this issue.
The group B data suggest that the antibody response may be influenced by prenatal PCB exposure, in part through its contribution to the accumulated PCB burden during the early postnatal period. The structural equation model suggested that the total perinatal exposure level was the best predictor. With regard to group A, the serum PCB concentration at age 7.5 y was still affected by prenatal and lactational transfer from the mother [15
], but the current or recent PCB levels appeared less predictive of decreased antibody concentrations than those at birth.
Taken together, these findings point to the PCB burden in the early postnatal period as the major determinant of immunotoxic effects. Although this conclusion would seem plausible [2
], the serum samplings were separated in time, and the exact timing of the greatest vulnerability cannot be determined from these data. In this regard, two immunological issues deserve consideration.
First, the importance of the thymus for the developing immune system is not restricted to the late gestational period, but includes early postnatal life [27
]. Thus, some specific thymus-related T cell functions could likely be vulnerable to PCB-mediated toxicity during early postnatal development.
Second, the priming by the first vaccine dose before the age of 6 mo is determined by the function of the immune system at that time. The efficacy of the priming will influence the magnitude of antibody production upon later boosting. Again, this consideration would support the notion that subsequent serum antibody concentrations could be negatively affected by early postnatal PCB exposure.
Although the PCB regressions for the two vaccine toxoids were not significantly different, the negative association of PCB exposure with the diphtheria antibody response seemed more pronounced than with the tetanus antibody response at 18 mo, while the reverse was the case at age 7.5 y. In addition to statistical uncertainty, these differences need to be interpreted in light of the relative antigenicity of the toxoids, the number of boosters received, and the stability of antibody concentrations induced. Tetanus toxoid may be regarded as a stronger antigen than diphtheria toxoid and is included in the Haemophilus influenzae vaccines. The tetanus antigen stimulation was therefore more pronounced, with average antibody concentrations being somewhat higher at age 7.5 y than at 18 mo. In contrast, the mean diphtheria antibody level at age 7.5 y was only one-third of the level seen at age 18 mo, supporting the notion that this toxoid is a weaker antigen.
At the age of 18 mo (group B) all children had reached a protective antibody level after diphtheria vaccination. However, the percentage of children with low (< 0.1 IU/ml) antibody levels at age 7.5 y was surprisingly high (21%), and children with insufficient antibody concentrations had a slightly increased PCB exposure. Had the study included a comparison group with much lower PCB exposure, the high percentage of Faroese children with low diphtheria antibody concentrations could perhaps have been convincingly linked to increased PCB exposure. With regard to tetanus, the children seemed to develop high antibody concentrations at age 18 mo, but the maintenance of this high level through age 7.5 y appears sensitive to PCB immunotoxicity.
In establishing acceptable intake levels for toxic substances, regulatory agencies often calculate limits based on a benchmark dose level and an uncertainty factor. The diphtheria antibody response at 18 mo showed a lower 95% confidence limit for the benchmark dose of the same order of magnitude as the one based on PCB-related neurodevelopmental deficits [22
]. With a default 10-fold uncertainty factor, the exposure limit would therefore be as low as 0.1 μg/g. Although PCB exposure levels have tended to decrease in many parts of the world [28
], the present results suggest that further efforts are needed to minimize this hazard.
This epidemiological study of healthy children provides evidence of pollutant-induced reduction of antibody production following routine childhood immunizations. Although subtle, such immune function impairment could become clinically important when the immune function is challenged by other factors such as preterm birth, chronic infection, or other disease. In addition, even slight impairments could be important at a population level, e.g., with regard to an increased prevalence of respiratory tract infections.