Salam, MT, Y-F Li, B Langholz and FD Gilliland. 2003. Early Life Environmental Risk Factors for Asthma: Findings from the Children's Health Study. Environmental Health Perspectives. doi:10.1289/ehp.6662 Online 9 December 2003.

Backgrounder on asthma
Press coverage

The US and other industrialized countries are experiencing an asthma epidemic. The incidence of asthma in Americans has roughly doubled since 1980. It is now the most common chronic disease in US children.

Many factors are known to provoke asthma attacks, but advances in scientific understanding of the underlying causes of the increase in asthma rates have been slow in coming. A number of hypotheses have been proposed, with exposures during infancy emerging as a important factor.

With this paper, Salam et al. report significant increases in asthma risk associated with exposures experienced early in childhood. Of the several risk factors they studied, the strongest associations they found were with exposures to herbicides and pesticides in infancy, and attending daycare before the age of 4 months old. Children exposed to herbicides before the age of 1 were 10 times more likely to develop early persistent asthma than controls.

Several features of their results are inconsistent with the 'hygiene' hypothesis... that better health care in childhood prevents the immune system from developing normally.

What did they do? Salam et al. conducted a case-control study of children in southern California. Cases were 279 children diagnosed with asthma before the age of 5 years. Of the cases, severity of asthma varied from early transient wheezing (~17% of cases) to late onset persistent asthma (24%) to early onset persistent asthma (60%).

Controls were 412 asthma-free children chosen to match the cases on a series of variables including grade, sex, community, and whether or not the child's mother smoked during pregnancy.

The child's biological mother was questioned by phone using a structured interview to obtain information about a range of possibly-relevant exposures along with demographic information. In the small percentage of cases where the mother was not present, interviewers questioned the father or care-giver.

What did they find?

Some basic observations about their study subjects:

• Most of their subjects were white, male and came from middle-income families.
• Asthmatic children were roughly twice as likely to come from families in which a parent or sibling had asthma.
• Neither family income nor the mother's level of education nor access to health care differed between cases and controls.
• Children with more siblings were less likely to devleop asthma.

Several types of exposure during infancy and early childhood substantially increased the risk that a child would develop asthma, based upon odds ratios Salam et al. calculated in comparing cases with controls.

The strongest association was for exposure to herbicides in the first year of infancy and early persistent asthma. Infants exposed to herbicides before the age of 1 were 10 times more likely to develop early persistent asthma. This result was highly significant, with 95% confidence intervals running from 2.46 to 41.33. Children exposed to herbicides after their first birthday,in contrast, were no more likely to develop asthma than controls. The odds ratio (OR)for all asthma types and exposure before the age of 1 was 4.58 (95% CI 1.36-15.43). In other words, children exposed to herbicides before the age of 1 were almost 5 times more likely to have asthma than controls.

Results for pesticide exposure were also significant but not as strong. Children exposed before 1 to pesticides were 3.58 times more likely to develop early persistent asthma than controls. As with herbicides, there was no increased risk of asthma if exposure began after the age of 1.

Exposures to farm animal, farm crop or dust exposure also elevated the risk of early persistent asthma, although the effect was not as pronounced as for pesticides and herbicides. The strongest of these was for exposure to farm animals in the first year or later (OR=3.03). The lower limits of the confidence intervals for these were at or above 1, but only marginally.

No exposures other than to pesticides, herbicides, and farm exposures bore a relationship with early persistent asthma. In contrast, the risk of early transient wheezing was elevated by exposure to "wood/oil smoke, soot or exhaust" exposure (odds ratio of 5.65 for exposure in the first year and later), cockroach exposure (with the largest odds ratio being 5.09, for exposures taking place at ages older than 1), and attending day care before the age of 4 months (OR= 5.36).

They found no association between asthma risk and whether or not the family had pets.

What does it mean? The most striking aspect of their finding is the strong association with herbicides and pesticides before the age of 1. This is the strongest association yet reported in a body of scientific literature in which there are few studies that have attempted to quantify early exposures to pesticides or herbicides and asthma risk in children. The authors observe:

That they found any association is remarkable because of the relatively crude nature of the survey instrument, a questionnaire. Normally, faulty recall would introduce statistical noise into the analysis, and render an association more difficult to find. The exception to this would be if parents of asthmatic children are more likely to remember herbicide/pesticide use than parents of controls. Where this the case, however, one might expect to see the effect on all asthma types for both ages (starting before age 1 yr, starting after age 1 yr), instead of only for early persistent asthma with exposure before age 1. Hence while biased recall can't be ruled out, it would appear to be unlikely.

The strength of the association is also remarkable because "pesticides" and "herbicides" include many very different compounds, not all of which would be likely to be increasing asthma risk. These data raise the possibility instead that there may be a small number of compounds for which the odds ratio are much greater. Then in an analysis like this, in which no distinction is made between herbicides that cause asthma and those that don't, their effect is averaged with other compounds and the observed OR is lower.

Three aspects of their findings are inconsistent with the "hygiene hypothesis,' that better hygiene early in life leads to fewer challenges to the developing immune system, which then predisposes the child to asthma:

• Children beginning day care before the age of 4 months are more likely to develop asthma. The hygiene hypothesis predicts that children in day care earlier should be less likely to develop asthma, because they would begin mingling at an earlier age with other children, would be exposed to more pathogens and hence more immune system challenges. Instead of supporting the hygiene hypothesis, this result instead raises questions about pesticide and herbicide applications in day care settings, questions which can't be answered with data from the current publication.
• Children exposed to farm animals and dust are more likely to develop asthma. The hygiene hypothesis predicts the opposite. Again, this raises questions about chemical exposures, which might co-vary with farm animals and dust.
• Children with no siblings were at lower risk to asthma than children with one or two siblings. As above, the hygiene hypothesis would predict that interactions with more children (in this case, siblings), would protect against asthma.

In contrast, the finding that once there was at least one sibling (as opposed to none), children with more siblings were less at risk to asthma is consistent with the hygiene hypothesis: presumably more siblings means more exposures. Many other factors covary with sibling number. As the authors point out, at the very least the finding that early day care attendance is associated with heightened risk, and that children with no siblings are at lower risk than those with one or two "suggests the need for a more complex "hygiene hypothesis."

[The high prevalence of asthma in inner city poverty centers also undermines this interpretation.]

The chief weaknesses of the study are its dependence upon parent recall and the lack of specificity about the details of exposure. Under most circumstances, these factors would make it false negatives more likely. Hence the strength of the associations discovered should be taken seriously.

While the study falls far short of establishing any causal relationships between exposures and asthma, it adds significantly to the evidence that exposures early in life may increase asthma risk and may thus may be contributing to the burgeoning asthma epidemic. Salam et al.'s work adds more broadly to the weight of evidence that exposures to herbicides and pesticides early in life can have adverse effects and should be avoided in the home and other settings.