Environmental Factors Develop Different Patterns of Immune Disease

I read with interest the article by Schmidt (2011) on the sprawling explosion of autoimmune diseases and its link to environmental exposure. Schmidt (2011) summarized the problematic state of the field: Systemic autoimmune diseases are common but thought rare; their clinical identification is far from the medical school description; and they continue to be identified as an autoantibody–target–manifestation scheme. Experience shows that a patient develops different autoantibodies through the lifespan, with different clinical patterns within each phase; deeper investigation shows that organ autoimmune disease is in fact systemic. Likewise, allergy, food intolerance, cancer, and immunodeficiency (all broad diseases that are immune in nature) cross and share autoimmunity. This suggests that immature immune systems are promoted and prevented from natural selection in the era of antibiotics, but they pay the cost of fostered health dysfunctions or diseases exposed to the current complex hostile environment. 
 
I noticed this complex scenario in a survey of 22 patients reporting sick building syndrome (Blasco 2011). Although reported data was limited to autoimmune cases and the involved substances were not yet identified, I found that the same environment triggered and worsened other immune disorders. The health of two patients with asthma inexplicably worsened when they started to work in the building. One patient developed gynecological cancer; another patient, who had a past history of Hodgkin’s lymphoma, developed chronic fever and fatigue again that lasted 3 years, until she was relocated. 
Some of the patients reported new adult onset of clinical intolerance of milk or other foods, and one patient was positive in a breath test for lactose intolerance. A review of family histories revealed that in 20% of the patients, more than one direct relative was affected by cancer. Personnel records showed that allergy was present in 59% of the patients; recurrent infections during childhood were common; 20% required amigdalectomy. One patient suffered rheumatic fever; one patient had not been effectively immunized after repeated hepatitis vaccines; and another had defective CD4 and suffered recurrent pneumococcal infections. 
 
It would be surprising if these illnesses did not share a common root in the immune system. Schmidt (2011) underlined rising prevalence rates of autoimmunity and discussed causes. I believe that this trend is relevant in general to immune disorders because of different reactions within the same scope of lymphocyte dysfunction in response to our new aggressive environment.

should include UV exposure, even absent specific FDA requirements.
Our resin data (resins P1. P2, P3, P4, P19, and P18) cited by Kelce and Borgert came from at least three replications of stress ing, extraction, and EA assays. As described in our "Methods" and "Supplemental Material," the assay variance was very small: SEs were typically smaller than the diameter of the data points of the graphed means. The whole series of 49 assays was repeated only once, but no extract exhibited EA; more recent extracts of the same plastics confirm our original results.
Kelce and Borgert noted that colorants are "embedded" in plastics. However, "bound" colorants in plastic compounds can and do readily leach from plastics. They are additives, which-like most additives-are only rarely chemically bound to polymers. Hence, con cerns about all additives are warranted because any can leach from a plastic product.
Regarding broader issues, the objective of our paper was to quantify the prevalence of xeno estrogen release from commonly used plastic products. These data are significant in part to help assess the risk of such products to human health and environmental con tamination. Kelce and Borgert cite Charles et al. (2007), who examined some inter actions between a small set of phyto estrogens and xeno estrogens. The limited negative results of that study have been contradicted by dozens of other studies (e.g., Patisaul and Jefferson 2010). However, our objective was not to establish definitive links between pub lic health issues, environmental pollution, and exposure to xenoestrogens. This relation ship is an active research area, and it will take many years to obtain definitive answers.
Kelce and Borgert's concerns about the paucity of epidemiological data correlating EA exposure via use of plastics with adverse human health effects is analogous to the long standing controversy for tobacco, which is now highly regulated, largely because increas ing numbers of epidemiological studies correlated smoking with heart disease and lung cancer. For decades, it was common to hear tobacco industry spokes persons argue that "[epidemiological] correlation does not mean causation" and demand that molecu lar, cellular, and/or systemic mechanisms be extensively demon strated before any action, regulatory or otherwise, be taken. One rarely hears spokespersons for the chemical and plastics industry make this argument for release of chemicals having EA from plastics, because the mechanisms by which tobacco has its effects are still much less well known compared to mechanisms by which chemi cals having EA produce adverse health and environ mental effects. Instead, we hear, "Where are the epidemiological correlations?" Those correlations are fewer (but not non existent) than for tobacco at this relatively young stage of the field, but the number of such publications is rapidly increasing. In the meantime, our study and hundreds to thousands of other in vitro studies demon strate that chemicals having EA have eas ily measurable effects on all sorts of human cells (including MCF7 cells). Most scientists in this field believe that such results suggest adverse health effects in humans and that, as such data continue to be gathered, these correlations will become as compelling as did those for the impact of tobacco smoking on public health.
Legislators, consumers, manufacturers, and scientists must judge current industry practices in this area based on available data. Reasonable people can differ. The American Chemistry Council takes the position that until definitive studies consistently show health and environmental hazards from chemi cals with EA leaching from plastic products, no industry action need be taken. We disagree. Plastic items are essential con sumer products, but we argue that they need to be made safer. Our most recent data show that there is very little extra expense to pro duce safer plastics that do not leach chemi cals having EA; that is, it costs very little at this time to avoid a potential health risk.  (2011) summarized the problematic state of the field: Systemic auto immune diseases are common but thought rare; their clinical identification is far from the medical school description; and they continue to be identified as an auto antibody-targetmanifestation scheme. Experience shows that a patient develops different auto antibodies through the lifespan, with different clinical patterns within each phase; deeper investiga tion shows that organ auto immune disease is in fact systemic. Likewise, allergy, food intol erance, cancer, and immuno deficiency (all broad diseases that are immune in nature) cross and share auto immunity. This suggests that immature immune systems are promoted and prevented from natural selection in the era of anti biotics, but they pay the cost of fos tered health dysfunctions or diseases exposed to the current complex hostile environment. I noticed this complex scenario in a sur vey of 22 patients reporting sick building syndrome (Blasco 2011). Although reported data was limited to auto immune cases and the involved substances were not yet identi fied, I found that the same environment trig gered and worsened other immune dis orders. The health of two patients with asthma inexplicably worsened when they started to work in the building. One patient developed gyneco logical cancer; another patient, who had a past history of Hodgkin's lymphoma, developed chronic fever and fatigue again that lasted 3 years, until she was relocated. Some of the patients reported new adult onset of clinical intolerance of milk or other foods, and one patient was positive in a breath test for lactose intolerance. A review of family histories revealed that in 20% of the patients, more than one direct relative was affected by cancer. Personnel records showed that allergy A 380 volume 119 | number 9 | September 2011 • Environmental Health Perspectives was present in 59% of the patients; recurrent infections during childhood were common; 20% required amigdalectomy. One patient suffered rheumatic fever; one patient had not been effectively immunized after repeated hepatitis vaccines; and another had defective CD4 and suffered recurrent pneumo coccal infections.

C.Z.Y. is employed by, and owns stock in, CertiChem (CCi) and PlastiPure (PPi
It would be surprising if these illnesses did not share a common root in the immune system. Schmidt (2011) underlined rising prevalence rates of auto immunity and dis cussed causes. I believe that this trend is rele vant in general to immune disorders because of different reactions within the same scope of lymphocyte dysfunction in response to our new aggressive environment.
The author declares that he has no actual or potential competing financial interests.  Rudel et al. (2011) is based on the concentration of DEHP metabolites-before correcting for creatinine levels. With little more than a sentence, Rudel et al. dismissed the accepted practice of correcting for crea tinine levels to account for the substantial variability in an individual's urine output. They suggested that such adjustment may "bias associations between urine metabo lite concentrations and age or sex" (Rudel et al. 2011) without explaining that the correction is widely used in urinary bio monitoring (by the Centers for Disease Control and most others) to improve the comparability of meas ure ments across individuals.

Luis M. Blasco
To their credit, Rudel et al. (2011) did conduct a compari son of the creatinine adjusted levels of DEHP metabolites and found no statistically significant difference in the mean levels of two of the three metabo lites before and after dietary intervention. The authors did not report the change in the adjusted levels of the third metabolite in the article.
The authors also did not address the variability in preintervention levels among the study participants. The presence of two individuals with very high metabolite levels clearly skewed the mean value upward and, consequently, exaggerated the significance of the intervention. Although Table 2 of Rudel et al. (2011) provides the minimum, mean, and maximum values, the variability is best seen in their Supplemental Material, Figure 3 (doi:10.1289/ehp.1003170), and on Silent Spring Institute's web site (Silent Spring Institute 2011). It is unfortunate that Rudel et al. (2011) chose not to address the vari ability in their article-and a bit surprisingbecause the post intervention increase in DEHP metabolites was significantly lower than the reported decrease (16% versus 56%). Steven Risotto, representing phthalate manufacturers for the American Chemistry Council (ACC), commented on our study that found a 3day diet with limited food packaging reduced participants' average bis(2ethyl hexyl) phthalate (DEHP) expo sure by > 50% (Rudel et al. 2011).

The author is employed by the American
Risotto's statement that creatinine adjust ment by normalization is accepted practice is misleading. Creatinine normali za tion is appropriate in a longitudinal study if the daily creatinine excretion of the partici pants remains approximately constant. That assumption is not reasonable in a dietary intervention because shortterm changes in diet can strongly influence creatinine levels (Kesteloot and Joossens 1993). In our article (Rudel et al. 2011), we addressed urinary dilution by including creatinine as a vari able in the mixedeffects model that estimates exposure reduction from the intervention, as currently recommended by researchers at the Centers for Disease Control and Prevention (Barr et al. 2005). Our analysis showed sig nificant decreases of 53-56% in the three DEHP metabo lites. Because creatinine nor malization is common, we also included nor malized results. Creatinine levels dropped significantly during the intervention, indicat ing that creatinine normalization artificially reduced the observed change. Nonetheless, results showed a 42-45% decrease in all three DEHP metabolites; the decrease was statistically significant for the most abun dant metabolite, MEHHP (mono(2ethyl 5hydroxy hexyl) phthalate).
Risotto also questions whether DEHP reductions are attributable to two individu als with high initial exposures. However, we reported the decreases in geometric means, which are not strongly influenced by a few high values. After removing these two participants, we still observed decreases of 37-42% in the geometric means of DEHP metabolites, and reductions in the two most abundant metabolites remain statistically sig nificant. Removing participants with high pre intervention exposures is appropriate if an unknown exposure may have covaried with the inter vention, but because the two highest exposures were in different families, such confounding seems unlikely.
As to why DEHP metabolite levels dropped during the intervention but did not increase significantly after the interven tion-as discussed in detail in our article (Rudel et al. 2011)-the discrepancy may be attributable to the differentlength "washout periods" (~ 48 hr between the beginning of the intervention and the first intervention urine sample, and ~ 36 hr between when participants resumed their regular diet and the first post intervention urine sample).
Risotto questions the public health signifi cance of our observed reduction in DEHP exposure. However, DEHP exposure levels in our study (Rudel et al. 2011)-and in the U.S. population-are similar to or higher than those recently reported to exceed health guidelines. Koch et al. (2011) found that 5 of 108 children studied had daily DEHP intakes in excess of the current U.S. Environmental Protection Agency reference dose, and 25% exceeded the tolerable daily