The results of the non-spatial analyses suggest that permitted discharges of chemical pollutants into surface waters are related to higher adjusted population mortality rates. More specifically, total non-cancer mortality is related to greater discharge quantities of chemicals classified as non-carcinogenic without need for toxicity weights or upstream discharges. For cancer mortality, the toxicity weights are necessary to detect associations between carcinogenic discharges and death rates, and for kidney disease mortality, both toxicity weights and area-weighted upstream discharges are necessary to detect discharge-mortality associations.
The cross-validation results suggest that chemicals not currently recognized as carcinogens may nevertheless play a role in contributing to cancer mortality risk. The potential carcinogenic properties of many chemicals are unknown and may be underestimated. Cross-validated results for kidney disease were significant but at a weaker level than for the non-cross-validation. There was a significant correlation between higher carcinogen releases and higher non-carcinogen releases (r = .69), so the cross-validation analysis of kidney disease may still be picking up non-carcinogen discharges. Some carcinogens such as cadmium or thallium are also recognized as causes of kidney damage . In contrast, the relatively small subset of known or suspected carcinogens was related to higher cancer mortality but not higher non-cancer mortality.
Kidney and total non-cancer death rates are most strongly related to discharges in rural areas not adjacent to metropolitan areas as compared to other urban-rural settings. It is possible that downstream effects from urban to rural areas may be a contributing factor, or downstream effects from one rural area to another.
The spatial analyses illustrate the wide variation of the local R2 values across the contiguous United States, as well as the variation in which model has the most explanatory power. The effects of both the chemical discharges and the covariates are not constant from one region of the country to another. Spatial models generally support the non-spatial analysis in that the releases of non-carcinogens are a better fit for the cancer mortality for most of the country (2303 out of 3109 counties) than the releases of carcinogens. For many of these counties, the improvement over not including any release variable is slight, indicating that the relative influence of chemical surface water discharges is small compared to effects of our covariates such as poverty or smoking rates. In many of the regions for which the improvement in local R2 was greatest, that improvement comes from the area weighted sum of all upstream releases of non-carcinogens, adjusted for toxicity. This suggests that for some, but not all, parts of the country, upstream releases may be an important factor.
A number of hypotheses may be suggested for future research based on the findings. First, studies may undertake whether chemicals currently not recognized as carcinogens may have carcinogenic properties. The number of chemicals with established carcinogenic information, whether that information is confirmatory or not, is small relative to the number of chemicals that are manufactured or used  There are many chemicals used in industrial processes or that are present in drinking water for which we have no information on health risks. The results of the current study can serve to encourage future research on understanding the possible health impacts for chemicals for which there is currently limited or no information. The choice of which chemicals to investigate may be guided by those which occur at highest levels, those for which information on related chemical properties suggests a possible health concern, or those chemicals which are more prevalent in regions of the country with the strongest relationship between the total chemical discharges and cancer mortality.
Second, the effects of co-exposures or mixtures of more than one chemical deserve further investigation. Most exposure research has focused on the effects of a single agent (lead, arsenic, benzo[a]pyrene, etc.), but there is increasing recognition that exposures to multiple agents simultaneously more closely matches what people actually experience in daily life , and that co-exposures may have additive or synergistic effects beyond single exposures, although research on this question is limited. The exposures in the current study were not isolated as to single agents because of the large number of possible agents to investigate and because release levels of any particular agent expressed on a national scale are usually small and are often concentrated in a few regions of the country.
Based on previous research, investigations of co-exposures may best be targeted initially to combinations of single agents about which there are known effects, especially when those agents are known to have similar health impacts such as manganese and lead co-exposure impacting neurodevelopment , or studies that investigate mixtures of single agents that are known individually to increase cancer risk such as arsenic , chromium(VI) , PAHs , tetrochloroethylene , or others.
Third, regional variations seen in the current study are intriguing but require future investigations to attempt to understand. The northern Great Plains area highlighted in
Figure 5 is one example. This area is largely rural and sparsely populated. It may be that rural areas, at least in some circumstances, are less impacted by environmental contaminants than urban areas, such that, when an environmental pollutant source (such as PCS discharges) is present in a rural area, that source represents a unique "spike" in exposures relative to background, whereas in urban areas with the same PCS pollutant source, the additional contribution of this source to health outcomes may be harder to detect against a background of other pollutants from industry or transportation.
Fourth, spatial variation in the contributions of area-weighted and on-site discharges suggests that area-weighted or upstream discharges may be important for some areas, whereas local discharges are more important for others (Figure 5). It is difficult to identify a pattern that can account for this variation; on-site discharges are relatively more important along the entire Mississippi River, but other major river systems don't show this pattern. Some major population centers are in areas where on-site discharges are more important, but other population centers are in areas where area-weighted scores had stronger effects. Regional variation in the composition of chemicals discharged may play a role in this spatial variation, as some chemicals or combinations of interacting chemicals may be present in one area but not in others. Regions to examine for these effects include the Northern Rockies and Arizona, where the measure of carcinogen releases instead of the non-carcinogen releases added substantial explanatory ability to the model, as well as areas in the Northern Plains and New England, which showed the strongest relationship between non-carcinogenic releases and cancer mortality. Similarly, there may be regional variation in how far downstream chemicals travel from the discharge site. Both properties of the chemical, such as its molecular weight, and properties of the stream, such as how fast it is flowing, could affect the distance the chemical travels. Accounting for molecular weight of airborne pollutants can improve models of atmospheric releases and public health outcomes , and a similar strategy may be useful when examining water-borne discharges.
Limits of the study include the ecological design, the selection of a partial list of chemicals with ingestion toxicity weights, the knowledge that the health impacts of mixtures are poorly understood, and the imperfect time relationships between discharges and mortality. Kidney disease was selected as one diagnostic sub-group for study but others, such as bladder cancer  could also have been investigated. We do not account for additional environmental variables that may be related to cancer or non-cancer risks, including geographic variation in levels of UV-B [20, 21], nitrates from non-point pollution agricultural sources , or traffic emissions. The results of the study must be taken as exploratory, but do show possible connections between greater permitted discharges of toxic chemicals into surface water and human health consequences, with potentially important geographic variations in the impacts of these discharges and in the particular discharges and health outcomes of greatest concern.