Concentration-Response Functions and Potential Thresholds

An important consideration in characterizing the public health impacts associated with NO2 exposure is whether the concentration-response relationship is linear across the full concentration range encountered or if nonlinear departures exist along any part of this range. Of particular interest is the shape of the concentration-response curve at and below the level of the current annual average standard of 0.053 ppm (53 ppb).

Human clinical studies typically provide individual-level response data in relation to different levels of NO2. The percentage of individuals showing responses across a range of NO2 exposures, the interindividual variability in response and the concentration at which an individual begins to respond can often be determined based on these studies. The previous assessment concluded that human clinical studies provided evidence that some asthmatics are more susceptible to the effects of NO2 but a concentration-response relationship was not evident (U.S. Environmental Protection Agency, 1993).

not well represented in human clinical studies or peculiarities in protocols necessary to elicit a response. Such peculiarities might include an unanticipated time course for a response not well captured in human clinical studies or other factors that influence a response that may not be measured in all human clinical studies (i.e., prior allergen sensitization by allergen or infectious agent).

Epidemiologic studies evaluate population-level responses, rather than individual responses. Low data density in the lower concentration range, response measurement error, exposure measurement error, and a shallow slope are some of the factors that complicated the ability to determine the shape of the concentration-response curve. A sigmoidal or S-shaped curve with a shallow slope may approximate linearity over a wide range of concentrations, making it difficult to characterize the exact nature of the concentration-response relationship. Biological characteristics that tend to linerarize concentration- response relationships include inter-individual variability, additivity of NO2- induced effects to a naturally occurring background of disease, and additivity to effects induced by other pollutant exposures.

Epidemiologic studies are generally consistent with a linear or log linear relationship between ambient NO2 concentration and the health outcome; however the shape of the NO2 concentration-response relationship has only been explored in several studies. To examine the shape of the concentration-

response relationship between NO2 and daily physician consultations for asthma and lower respiratory disease in children, Hajat et al. (1999) used bubble plots to examine residuals of significant models plotted against moving averages of NO2 concentration. They noted a weak trend for asthma and 0-1 day moving average lag of NO2 and proposed that effects are weaker at lower concentrations and stronger at higher concentrations than predicted by the linear model. These departures were in accord with the shape of the sigmoidal dose-response model below the median effective dosage.

Several studies of ED visits or hospitalizations for cardiac or respiratory disease examined the shape of the concentration-response curve. Burnett et al. (1997a) used the locally estimated smoothing splines (LOESS) to describe the concentration-response for respiratory and cardiac hospitalizations for the summers of 1992-94 in Toronto. Both graphs showed a smaller slope at lower concentrations, but a chi-square test detected no significant difference between the LOESS and a linear effect. In another study of respiratory hospitalizations in 16 Canadian cities, Burnett et al. (1997b) were unsuccessful in

identifying the shape of the concentration-response function, i.e. a linear effect was not significant nor did inclusion of a quadratic term improve the fit of the model. In another study of hospitalizations for CHF in 10 Canadian cities, Burnett et al. (1997c) found that a logarithmic concentration-response model, which has a steeper slope at lower concentrations, provided the best fit for the data compared to the other forms of the model examined. In a study among Medicaid-enrolled asthmatics in two urban cities in Ohio, Jaffe et al. (2003) found that when a concentration-response relationship was examined by quintile of NO2 concentration, no consistent pattern was found. Tenías et al. (1998) also reported no consistent pattern in their study of the association between ambient NO2 and ED visits in Valencia’s Hospital Clìnic

Universitari from 1994 to 1995. Castellsague et al. (1995) found a small but significant association of NO2 and ED visits due to asthma in Barcelona. Specifically, the adjusted risk estimates of asthma visits for each quartile of NO2 showed increased risks in each quartile for the summer months, but not the winter months. Together these studies indicate some disagreement in the trend of the concentration- response curve below 50 ppb 24 h NO2.

Samoli et al. (2003) examined the relationship between mortality and NO2 in a subset of 9 European cities out of 30 APHEA cities. The cities were selected to have overlapping NO2 ranges to improve the detection of nonlinearity. They found the linear assumption to be adequate for these cities. Kim et al. (2004b) investigated non-linearity in relationships between air pollutants and mortality in Seoul, Korea, by analyzing data using a log-linear Generalized Additive Model (GAM; linear model), a cubic natural spline model (nonlinear model), and a B-mode splined model (threshold model). They did not detect a nonlinear association for NO2 with mortality.

In conclusion, of the epidemiology studies that attempted to look at the shape of the concentration- response below 50 ppb, one indicated that effects were weaker at lower levels (Hajat et al. 1999), and one

linear function best described the data (Burnett et al. 1997a,b; Jaffe et al. 2003; Tenias et al., 1998; Castellsague et al., 1995). These results do not provide adequate evidence to suggest that nonlinear departures exist along any part of this range of NO2 exposure concentrations. Evidence from human clinical studies has not helped to clarify understanding of the concentration-response function of NO2 (see chapter 3).