Research on Multiple Chemical Sensitivity (MCS)

Compiled by

Professor Anne C. Steinemann and Amy L. Davis

University of Washington

This document lists scientific citations for peer-reviewed journal articles that support a physiological basis for MCS:

1. Abdel-Rahman A., Shetty A.K., Abou-Donia M.B. 2002. Disruption of the blood-brain barrier and neuronal cell death in cingulate cortex, dentate gyrus, thalamus, and hypothalamus in a rat model of Gulf-War syndrome. Neurobiology of Disease 10(3): 306-26.
2. Abel-Rahman A., Abou-Donia S., El-Masry E., Shetty A., Abou-Donia M. 2004. Stress and combined exposure to low doses of pyridostigmine bromide, DEET, and permethrin produce neurochemical and neuropathological alteration in cerebral cortex, hippocampus, and cerebellum. Journal of Toxicology and Environmental Health Part A 67(2): 163-92.
3. Abdel-Rahman A., Dechkovskaia A.M., Goldstein L.B., Bullman S.H., Khan W., El-Masry E.M., Abou-Donia M.B. 2004. Neurological deficits induced by malathion, DEET, and permethrin, alone or in combination in adult rats. Journal of Toxicology and Environmental Health Part A 67(4): 331-56.
4. Abou-Donia M.B 2003. Organophosphorus ester-induced chronic neurotoxicity. Archives of Environmental Health 58(8): 484-97.
5. Abou-Donia M.B., Wilmarth K.R., Abdel-Rahman A.A., Jenseen K.F., Oehme F.W., Kurt T.L. 1996. Increased neurotoxicity following concurrent exposure to pyridostigmine bromide, DEET, and chlorpyrifos. Fundamentals of Applied Toxicology 34(2): 201-22.
6. Abou-Donia M.B., Dechkovskaia A.M., Goldstein L.B., Shah D.U., Bullman S.L., Khan W.A. July 2002. Uranyl acetate-induced sensorimotor deficit and increased nitric oxide generation in the central nervous system in rats. Pharmacology, Biochemistry, and Behavior 72(4): 881-90.
7. Abou-Donia M.B., Dechkovskaia A.M., Goldstein B., Abdel-Rahman A., Bullman S.L., Khan W.A. 2004. Co-exposure to pyridostigmine bromide, DEET, and/or permethrin causes sensorimotor deficit and alterations in brain acetylcholinesterase activity. Pharmacology, Biochemistry, and Behavior 77(2): 253-62.
8. Abu-Qare A.W., Abou-Donia M.B. 2001. Combined exposure to sarin pyridostigmine bromide increased levels of rat urinary 3-nitrotyrosine and 8-hydroxy-2’deoxyguanosine, biomarkers of oxidative stress. Toxicology Letters 123(1): 51-58.
9. Abu-Qare A.W., Abou-Donia M.B. 2001. Biomarkers of apoptosis: release of cytochrome c, activation of caspase-3, induction of 8-hydroxy-2′-deoxyguanosine, increased 3-nitrotyrosine, and alteration of p53 gene. Journal of Toxicology and Environmental Health Part B, Critical Reviews 4(3): 313-32.
10. Abu-Qare A.W., Abou-Donia M.B. 2008. In vitro metabolism and interactions of pyridostigmine bromide, N,N-diethyl-m-toluamide, and permethrin in human plasma and liver microsomal enzymes. Xenobiotica 38(3): 294-313.
11. Anderson R.C., Anderson J.H. 1999. Sensory irritation and multiple chemical sensitivity. Toxicology and Industrial Health 15(3-4): 339-45.
12. Ashford N.A. 1999. Low-level chemical sensitivity: implications for research and social policy. Toxicology and Industrial Health 15(3-4): 421-47.
13. Baldwin C.M. and Bell I.R. 1998. Increased cardiopulmonary disease risk in a community-based sample with chemical odor intolerance: implications for women’s health and health-care utilization. Archives of Environmental Health 1998 53(5): 347-53.
14. Baldwin C.M., Bell I.R., O’Rourke M.K. 1999. Odor sensitivity and respiratory complaint profiles in a community-based sample with asthma, hay fever, and chemical odor intolerance. Toxicology and Industrial Health 15(3-4): 403-9.
15. Bascom R., Meggs W.J., Framptom M., Hudnell K., Kilburn K., Kobal G., Medinsky M., Rea W. 1997. Neurogenic inflammation: with additional discussion of central and perceptual integration of nonneurogenic inflammation. Environmental Health Perspective 105 (Suppl. 2): 531-37.
16. Bell I.R., Miller C.S., and Schwartz G.E. 1992. An olfactory-limbic model of multiple chemical sensitivity syndrome: possible relationships to kindling and affective spectrum disorders. Biological Psychiatry 32(3): 218-42.
17. Bell I.R., Warg-Damiani L., Baldwin C.M., Walsh M.E., Schwartz G.E. 1998. Self-reported chemical sensitivity and wartime chemical exposures in Gulf War veterans with and without decreased global health ratings. Military Medicine 163(11): 725-32.
18. Bell I.R., Schwartz G.E., Peterson J.M. and Amend D. 1993. Self-reported illness from chemical odors in young adults without clinical syndromes or occupational exposures. Archives of Environmental Health. 48(1): 6-13.
19. Bell I.R., Schwartz G.E., Baldwin C.M., Hardin E.E. 1996. Neural sensitization and physiological markers in multiple chemical sensitivity. Regulatory Toxicology and Pharmacology 24(1), pt. 2: S39-S47.
20. Bell I.R., Baldwin C.M., Schwartz G.E.R. 2001. Sensitization studies in chemically intolerant individuals: implications for individual difference research. Annals of the New York Academy of Sciences 933:38-47.
21. Brandt-Rauf P.W., Andrews L.R., Schwarz-Miller J. 1991. Sick-hospital syndrome. Journal of Occupational Medicine 33(6): 737-39.
22. Bronstein A.C. 1995. Multiple chemical sensitivities—new paradigm needed. Journal of Toxicology: Clinical Toxicology 33(2): 93-94.
23. Brooks S.M., Weiss M.A., Bernstein I.L. 1985. Reactive airways dysfunction syndrome. Case reports of persistent airways hyperreactivity following high-level irritant exposures. Journal of Occupational Medicine 27(7): 473-76.
24. Brown-DeGagne A.M., McGlone J. 1999. Multiple chemical sensitivity: a test of the olfactory-limbic model. Journal of Occupational and Environmental Medicine 41(5): 366-77.
25. Buchwald D., Garrity D. 1994. Comparison of patients with chronic fatigue syndrome, fibromyalgia, and multiple chemical sensitivities. Archives of Internal Medicine 154(18): 2049-53.
26. Caress S.M., Steinemann A.C. 2003. A review of a two-phase population study of multiple chemical sensitivities. Environmental Health Perspectives 111(12): 1490-97.
27. Caress S.M., Steinemann A.C. 2004. Prevalence of multiple chemical sensitivities: A population-based study in the southeastern United States. American Journal of Public Health 94(5): 746-47.
28. Caress S.M., Steinemann A.C. 2009. Prevalence of fragrance sensitivity in the American population. Journal of Environmental Health 71(7): 46-50.
29. Caress S.M., Steinemann A.C. 2009. Asthma and chemical hypersensitivity: prevalence, etiology, and age of onset. Toxicology and Industrial Health 25(1): 71-78.
30. Caress S.M., Steinemann A.C. 2004. A national population study of the prevalence of multiple chemical sensitivity. Archives of Environmental Health 59(6): 300-305.
31. Caress S.M., Steinemann A.C. 2005. National prevalence of asthma and chemical hypersensitivity: an examination of potential overlap. Journal of Occupational and Environmental Medicine 47(5): 518-22.
32. Caress S.M., Steinemann A.C., Waddick C. 2002. Symptomatology and etiology of multiple chemical sensitivities in the southeastern United States. Archives of Environmental Health 57(5): 429-36.
33. Davidoff A.L., Keyl P.M., Meggs W.J. 1998. Development of multiple chemical sensitivities in laborers after acute gasoline fume exposure in an underground tunneling operation. Archives of Environmental Health 53(3):183-89.
34. DeRosa C.T., Hicks H.E., Ashizawa A.E., Pohl H.R., Mumtaz M.M. 2006. A regional approach to assess the impact of living in a chemical world. Annals of the New York Academy of Sciences 1076:829-38.
35. Donnay A.H. 1999. On the recognition of multiple chemical sensitivity in medical literature and government policy. International Journal of Toxicology 18(6): 383-92.
36. Elberling J., Linneberg A., Dirksen A., Johansen J.D., Frølund L., Madsen F., et al. 2005. Mucosal symptoms elicited by fragrance products in a population-based sample in relation to atopy and bronchial hyper-reactivity. Clinical and Experimental Allergy 35(1): 75-81.
37. Farrow A., Taylor H., Northstone K., Golding J. 2003. Symptoms of mothers and infants related to total volatile organic compounds in household products. Archives of Environmental Health 58(10): 633-41.
38. Fernandez M., Bell I.R., Schwartz G.E. 1999. EEG sensitization during chemical exposure in women with and without chemical sensitivity of unknown etiology. Toxicology and Industrial Health 15(3-4): 305-12.
39. Gibson P.R., Elms A.N., Ruding L.A. 2003. Perceived treatment efficacy for conventional and alternative therapies reported by persons with multiple chemical sensitivity. Environmental Health Perspectives 111(12): 1498-1504.
40. Gilbert M.E. 1995. Repeated exposure to lindane leads to behavioral sensitivities and facilitates electrical kindling. Neurotoxicolgy and Teratology 17(2): 131-41.
41. Greene G.J., Kipen H.M. 2002. The vomeronasal organ and chemical sensitivity: a hypothesis. Environmental Health Perspectives 110 (Suppl 4): 655-61.
42. Haley R.W., Billecke S., La Du B.N. 1999. Association of low PON1 type Q (type A) arylesterase activity with neurologic symptoms complexes in Gulf War veterans. Toxicology and Applied Pharmacology 157(3): 227-33.
43. Heuser G., Mena I., Alamos F. 1994. NeuroSPECT findings in patients exposed to neurotoxic chemicals. Toxicology and Industrial Health 10: 561-71.
44. Jammes Y., DelPierre S., DelVolgo M.J., Humbert-Tena C., Burnet, H. 1998. Long-term exposure of adults to outdoor air pollution is associated with increased airway obstruction and higher prevalence of bronchial hyperresponsiveness. Archives of Environmental Health 53(6): 372-77.
45. Johansson A., Löwhagen O., Millqvist E., Bende M. 2002. Capsaicin inhalation test for identification of sensory hyperreactivity. Respiratory Medicine 96(9): 731-35.
46. Joffres M.R., Sampalli T., Fox R.A. 2005. Physiologic and symptomatic responses to low-level substances in individuals with and without chemical sensitivities; a randomized controlled blinded pilot booth study. Environmental Health Perspectives 113(9): 1178-83.
47. Kelly K.J., Prezant D.J. 2005. Bronchial hyperreactivity and other inhalation lung injuries in rescue/recovery workers after the world trade center collapse. Critical Care Medicine 33 (Suppl 1): S102-S106.
48. Kilburn K.H. 2003. Effects of hydrogen sulfide in neurobehavioral function. Southern Medical Journal 90(10): 997-1106.
49. Kilburn K.H. 1999. Measuring the effects of chemicals in the brain. Archives of Environmental Health 54(3): 150. Read more…

Many parents worry about their child’s exposure to phthalates, the chemical compounds used as plasticizers in a wide variety of personal care products, children’s toys, and medical devices. Phthalate exposure can begin in the womb and has been associated with negative changes in endocrine function. A new study soon to be published in the Journal of Pediatrics examines the possibility that in utero phthalate exposure contributes to low birth weight in infants. Low birth weight is the leading cause of death in children under 5 years of age and increases the risk of cardiovascular and metabolic disease in adulthood.  

To investigate the associations between in utero phthalate exposure and low birth weight, Dr. Renshan Ge of the Population Council and colleagues from Fudan University and Second Military Medical University in Shanghai studied 201 pairs of newborns and their mothers between 2005 and 2006. Of the 201 infants studied, 88 were born with low birth weight. The researchers analyzed samples of the infants’ meconium, the first bowel movement that occurs after birth, and cord blood to determine phthalate levels.  

They found quantifiable levels of phthalate and phthalate metabolites in more than 70% of the samples. Infants with low birth weight had consistently higher levels of phthalates. According to Dr. Ge, “The results showed that phthalate exposure was ubiquitous in these newborns, and that prenatal phthalate exposure might be an environmental risk factor for low birth weight in infants.” Although these associations are not conclusive, this study supports the accelerating efforts to minimize phthalate exposure. 

Reference: The study, reported in “Phthalate Levels and Low Birth Weight: A Nested Case-Control Study of Chinese Newborns” by Zhang Y, PhD, Lin L, MD, Cao Y, PhD, Chen B, MD, Zheng L, MSC, Ge R, MD, appears in the Journal of Pediatrics, DOI 10.1016/j.jpeds.2009.04.007, published by Elsevier. EurekAlert, June 25, 2009.

Manufactured nanoparticles can be toxic via interactions with proteins and enzymes. Acetylcholinesterase (AChE) is a key enzyme present in the brain, blood and nervous system. Therefore, adsorption and inhibition of AChE by eight nanoparticles, SiO(2), TiO(2), Al(2)O(3), Al, Cu, Cu-C (carbon-coated copper), multi-walled carbon nanotubes (MWCNT) and single-walled carbon nanotubes (SWCNT), were examined.

A modified Ellman assay was used to measure AChE activity because nanoparticles could adsorb the yellowish product, 5′-mercapto-2′-nitrobenzoic acid (5-MNBA) during the color development. Adsorption and inhibition rates by nanoparticles were estimated by decrease of AChE activities compared to controls.

Carbon nanotubes had high affinity for AChE adsorption, the highest being SWCNT (94%). Nano SiO(2) and Al(2)O(3) showed the lowest adsorption. Inhibition by the tested nanoparticles was primarily caused by adsorption.

However, Cu(2+) release in Cu and Cu-C nanoparticle suspensions caused 40% and 45% of AChE activity reduction, respectively. AChE inhibition by bulk Cu and activated carbon particles was also measured for comparison, showing that the inhibition by bulk particles was lower than their counterpart nanoparticles. For bulk Cu particles, AChE inhibition was primarily caused by dissolved ions, but mainly by adsorption for activated carbon.

AChE inhibition by Cu, Cu-C, MWCNT and SWCNT had dose-response relationships, and their median inhibitory concentrations (IC(50)) were 4, 17, 156 and 96mgL(-1), respectively, showing that these nanoparticles may have neurotoxicity and AChE may have potential to be used as a biomarker for nanoparticles.

Reference: Wang Z, Zhao J, Li F, Gao D, Xing B., Adsorption and inhibition of acetylcholinesterase by different nanoparticles, College of Environmental Science and Engineering, Ocean University of China, Qingdao 266100, China, Chemosphere. 2009 Jun 18.

Although it is known that infants are more susceptible than adults to the toxic effects of pesticides, this increased vulnerability may extend much longer into childhood than expected, according to a new study by researchers at the University of California, Berkeley.

Among newborns, levels of paraoxonase 1 (PON1), an enzyme critical to the detoxification of organophosphate pesticides, average one-third or less than those of the babies’ mothers. It was thought that PON1 enzyme activity in children approached adult levels by age 2, but instead, the UC Berkeley researchers found that the enzyme level remained low in some individuals through age 7.

Based upon the findings, reported this month in the journal Environmental Health Perspectives, the study authors recommend that the U.S. Environmental Protection Agency (EPA) re-evaluate the current standards for acceptable levels of pesticide exposure.

“Current EPA standards of exposure for some pesticides assume children are 3 to 5 times more susceptible than adults, and for other pesticides the standards assume no difference,” said Nina Holland, UC Berkeley adjunct professor of environmental health sciences and senior author of the paper. “Our study is the first to show quantitatively that young children may be more susceptible to certain organophosphate pesticides up to age 7. Our results suggest that the EPA standards need to be re-examined to determine if they are adequately protecting the most vulnerable members of the population.”

In 2001, the EPA began restricting organophosphate pesticides in products sold for use in homes, mainly because of risks to children. However, organophosphate pesticides, such as chlorpyrifos and diazinon, are still used in agriculture in the United States and elsewhere.

The study, conducted by UC Berkeley’s Center for the Health Assessment of Mothers and Children of Salinas (CHAMACOS), involves 458 children from an agricultural region who were followed from birth through age 7. Cord blood samples were collected from all children to determine their PON1 genotype and to obtain baseline measures of the enzyme’s activity level.

For more than 100 of the children in the study, researchers were able to obtain at least four additional measurements – at ages 1, 2, 5 and 7 – of PON1 activity. Almost all the children in the study had 2 to 3 time points assessed, for a total of 1,143 measurements of three types of PON1 enzyme activity.

One’s PON1 genotypic profile determines how effectively the enzyme can metabolize toxins. For example, people with two copies of the Q form of the gene – known as a QQ genotype – produce a PON1 enzyme that is less efficient at detoxifying chlorpyrifos oxon, a metabolite of chlorpyrifos, than the enzyme produced by people with two R forms of the gene. Similarly, individuals with two T forms of the PON1 gene on a different part of the chromosome generally have a lower quantity of the enzyme than do those with two C forms of the gene.

Previous research led by Holland found that some of the QQ newborns may be 50 times more susceptible to chlorpyrifos and chlorpyrifos oxon than RR newborns with high PON1 levels, and 130 to 164 times more susceptible than some of the RR adults.

Of the children in this latest study, 24 percent had the QQ genotype, and 18 percent had the TT genotype, both of which are associated with lower activity of the PON1 enzyme. Moreover, 7.5 percent of the children had both QQ and TT genotypes, which is considered an even more vulnerable profile.

On average, the quantity of enzyme quadrupled between birth and age 7. The greatest rise in enzyme activity was among children with the RR and CC variants of the PON1 gene, which quickly outpaced the increase in children with the QQ and TT genotypes.

The fact that enzyme activity remained low for certain kids with vulnerable genotypes well past age 2 was surprising for the study authors. The researchers are continuing to collect data for these children as they grow older to see if the pesticide susceptibility continues.

“In addition to its involvement in the metabolism of pesticides, many studies are now finding that PON1 may play an important role in protecting against oxidative stress, which is linked to diseases from asthma to obesity and cardiovascular disease,” said study lead author Karen Huen, a UC Berkeley Ph.D. student in environmental health sciences. “The children in our study whose genotypes are related to lower PON1 activity may not only be more susceptible to pesticides throughout much of their childhood, they may also be more vulnerable to other common diseases related to oxidative stress.”

Notably, other studies have found that PON1 genotypes vary by race and ethnicity, with the Q variants more common among Caucasians, less common among Latinos, and least common among African Americans. The majority of the subjects in this study were Mexican-American.

“What’s important about this study is that it shows that young children are potentially susceptible to certain organophosphates for a longer period of time than previously thought,” said Brenda Eskenazi, UC Berkeley professor of epidemiology and director of CHAMACOS and the Center for Children’s Environmental Health Research. “Policymakers need to consider these vulnerable populations when establishing acceptable levels of exposure to different pesticides.”

Funding from the National Institute of Environmental Health Sciences and the EPA helped support this research.

Reference: UC Berkeley, Children susceptible to pesticides longer than expected, study finds, June 22, 2009

Tobacco is an important cash crop of Pakistan. Pesticides are commonly used to increase the crop yield, but their health impact has not been studied yet.  

The objectives of the study were to determine the frequency of pesticide poisoning and to explore the knowledge, attitudes and practices (KAP) towards safety measures among the tobacco farmers in Swabi, Pakistan.  

One hundred and five tobacco farmers involved in pesticide application were randomly selected from two villages of district Swabi. A structured questionnaire was used for clinical and KAP information. Plasma cholinesterase (PChE) levels were measured by Ellman’s method by using GD Italy kits. All tobacco farmers were males with a mean (SD) age of 26 (9) years.  

The majority of the farmers reported multiple symptoms headache, dizziness, vomiting, shortness of breath, muscle weakness and skin rash correlate with the clinically significant depression of PChE levels. 

Out of 105 pesticide applicators, 58 (55%) had post-exposure reduction in PChE levels <20% from baseline, 35 (33%) had mild poisoning (20-40% reduction) and 12 (11%) had moderate poisoning (>40% reduction).  

Most of the farmers did not use any personal protective equipment during pesticide handling. Only a few used shoes (31%), masks (14%) and gloves (9%) during pesticide spray.  

In conclusion, the tobacco farmers had mild to moderate pesticide poisoning, which was correlated with depression in PChE levels. Moreover, most farmers had little knowledge about the safety measures, casual attitude and unsatisfactory safety practices with regard to the use of basic protective equipments during pesticide applications on the tobacco crop. 

Reference: Khan DA, Shabbir S, Majid M, Naqvi TA, Khan FA., Risk assessment of pesticide exposure on health of Pakistani tobacco farmers, aDepartment of Pathology, Army Medical College, NUST, Rawalpindi, Pakistan, Journal of Exposure Science and Environmental Epidemiology advance online publication, 17 June 2009; doi:10.1038/jes.2009.13.