Toxic Nonmetal Chemicals: New Comprehensive Testing Available

by William Shaw, PhD

Screening for a wide variety of toxic metals has been available for many decades, first by atomic absorption and later by mass spectrometry. The availability of such testing allowed integrative and environmentally oriented physicians to solve clinical problems of their patients who had not experienced adequate resolution of their severe medical symptoms through “conventional” medicine, largely through the use of metal chelating agents.

However, the availability of an economical, accurate, and fast screening tool for a wide range of nonmetal toxic chemicals prevalent in the environment lagged considerably behind. Many environmental chemicals could be tested individually, but the vast majority of people are exposed to a wide variety of chemicals in food, water, and air. Since many of the symptoms of nonmetal toxic exposures are similar, what type of testing should a physician order?

If 50 different chemicals were tested at a typical price of $100, the total price would be $5000. With insurance companies now notoriously tightfisted about paying for unusual testing, it is to be expected that most or all of this testing would be denied coverage. Another common consideration is that such testing may not give any indication of the overall clinical severity of the total toxic exposure. New testing from the Great Plains Laboratory addresses many of these considerations. First, it screens for 168 toxic chemicals in a single urine sample, using state-of-the-art, high-performance liquid chromatography coupled with triple quadrupole mass spectrometry. This includes screening for over 150 organophosphate pesticides, benzene, styrene, xylene, the herbicide 2,4-dichlorophenoxyacetic acid (2,4-D), monoethylphthalate (a major metabolite of the toxic plasticizer diethyl phthalate), six different pyrethroids, and the common gasoline additives MTBE and ETBE.

Organophosphate pesticides are one of the most common insecticides used worldwide. In 2013, the American Association of Poison Control Centers’ National Poison Data System reported 2354 single exposures to organophosphate insecticides alone.¹ Two cases were fatal. There were also 578 single exposures to organophosphate insecticides in combination with other insecticides. Of all those exposures, 715 occurred in children younger than 6 years. Organophosphate are widely used in agriculture. EPA data indicate that 35% of apples tested in 2009 had detectable organophosphate residue.² Undoubtedly, many exposures to organophosphates go undetected. Organophosphates react with the hydroxyl group of the amino acid serine that is found in all proteins. Many of the severe clinical effects of organophosphate pesticides are due to the reaction of these compounds with acetylcholinesterase, an enzyme found in both the peripheral parasympathetic nervous system as well as the central nervous system. The initial reaction of organophosphates with acetylcholinesterase is reversible. However, a nonenzymatic reaction between the organophosphate and acetylcholinesterase results in an “aging” reaction such that the enzyme is permanently deactivated. The symptoms of organophosphate poisoning are due to a marked excess of acetylcholine as its receptors are over stimulated leading to diarrhea, sweating, lacrimation, and vomiting. Other symptoms include anxiety, headache, convulsions, ataxia, impaired respiration and circulation, and tremor. Associations between organophosphate exposures have also been made for attention deficit with hyperactivity, autism spectrum disorders, impaired fertility, decreased IQ, brain structure abnormalities, psychosis, and depression.^3–6 An example of the value of such testing is given in Table 1. The patient was a 2-year-old child with autism. Toxic chemical exposure is not usually anticipated in a 2-year-old child. The results in Table 1 indicated abnormally elevated values in the urine for the major metabolite of vinyl chloride as well as the major metabolite of many organophosphates. Organophosphate exposure has been connected with mitochondrial damage.^7,8 In addition, the urine of the child had detectable values for metabolites of the gasoline additives MTBE and ETBE, diethylphthalate, styrene, benzene, and xylene (data not shown). The urine of the child also contained extremely high values for a very sensitive marker for mitochondrial damage called tiglylglycine (TG); elevated values indicate mitochondrial dysfunction.⁹ Organic acid testing on the same urine sample revealed high concentrations of lactic acid and high values of the Krebs cycle metabolites succinic acid, fumaric acid, and aconitic acid which are also consistent with mitochondrial damage.

Table 1:

Results of Toxic Chemical Analysis on a Child with Autism

* Ratio is patient’s value divided by the 95th percentile of the reference range.

Both vinyl chloride and diethylphosphate have been associated with autism spectrum disorders based on epidemiological studies.^10,11 To my knowledge, this appears to be the first case study confirming the presence of either of these chemicals at high concentrations in a child with autism and associating these toxic chemicals with a high concentration of a biochemical marker, tiglylglycine, that is a marker for mitochondrial dysfunction. Autism has previously been reported to be associated with mitochondrial damage, and both vinyl chloride and organophosphate have been associated with mitochondrial damage.^7,812,13 It is interesting that in one of the cases in which the US Department of Health and Human Services (DHHS) made a substantial vaccine damage award to the parents of a child who developed autism shortly after receiving multiple vaccines, the child was later found to have had substantial mitochondrial dysfunction.¹⁴

Vinyl chloride is one of the most abundant industrial chemicals on earth, with more than 13 billion kilograms produced annually. Its main industrial use is the production of polyvinyl chloride (PVC), which is used for a variety of plastic products, including pipes, wire and cable coatings, and packaging materials. PVC plastics are somewhat rigid so that plasticizers, predominantly phthalates are frequently added to PVC to obtain better flexibility. Most phthalates are also toxic. In the study on autism, people who lived in homes with PVC floors were more likely to have a child with autism.¹⁵ It is known that vinyl chloride monomer becomes entrapped in PVC dust and can be released slowly over time, and vinyl chloride exposure is associated with angiosarcoma of the liver in both humans and animals.¹⁶ Other organs for which there is increased cancer risk with vinyl chloride exposure include the liver, brain, and lung, and probably the lymphohematopoietic system. Liver damage, severe neurologic disorder, and angioneuropathy have also been associated with increased vinyl chloride exposure.

Pyrethroids are insecticidal chemicals with similarities to naturally occurring pyrethrins but which possess greater toxicity to insects and mammals. Pyrethrum is the term used to describe a crude extract of the chrysanthemum flower, which was used by the Chinese for thousands of years. The term pyrethrins refers to at least six insecticidal chemicals isolated from pyrethrum. The Agency for Toxic Substances and Disease Registry (ATSDR), the US federal agency that distributes information about toxic chemicals, lists the symptoms associated with pyrethroid exposure: feelings of numbness, itching, burning, stinging, tingling, or warmth that could last for a few hours, dizziness, headache, and nausea that might last for several hours, muscle twitching, reduced energy, changes in awareness, loss of consciousness, incoordination, tremors, convulsions, allergic reactions, and death.¹⁷

Müller-Mohnssen and Hahn indicate that exposure to pyrethroids can cause neurological symptoms, locomotory disorders reminiscent of multiple sclerosis or Parkinson’s and sensory, motor, and vegetative polyneuropathy, leading, for instance, to cardiovascular regulatory disorder.¹⁸ Nonneurological symptoms include immunosuppression with consecutive opportunistic infections, such as Candida albicans, most frequently of the alimentary tract, but also dermal and mucosal swellings, lichen-ruber-like efflorescences, loss of hair, and conjunctivitis. Other symptoms are hypoglycemic crises, inhibition of fertility, disturbances of blood clotting, and, most frequently in children, suspected hematopoietic disorders. Children with pyrethrins metabolite concentration above the limit of detection were twice as likely to have ADHD, and hyperactive-impulsive symptoms increased by 50% for every 10-fold increase in pyrethrin metabolites.¹⁹ The effects of pyrethroids in this study were sex specific: pyrethroid biomarkers were associated with increased odds of an ADHD diagnosis and number of ADHD symptoms for boys but not girls.

The pesticide 2,4-dichlorophenoxyacetic acid (2,4-D) is a common systemic herbicide used in the control of broadleaf weeds. It is one of the most widely used herbicides in the world and is a possible carcinogen.²⁰ Since 2014, Enlist Duo, a herbicide product which contains a 2,4-D salt and glyphosate, has been approved in Canada and the US for use on soybeans and maize that were genetically modified to be resistant to both 2,4-D and glyphosate. Men who work with 2,4-D are at risk for abnormally shaped sperm and impaired fertility.²¹ A cohort study found increased risk of ALS among workers exposed to the herbicide 2,4-dichlorophenoxyacetic acid (2,4-D) compared with other company employees and found that 2,4-D interfered with myelination in the brain of animals as the result of lactational exposure.^22–24 There were changes in behavior patterns of animals that included apathy, reduced social interaction, repetitive movements, tremors, and immobility in pups exposed to 2,4-D.²⁵ Neuritis, weakness, nausea, abdominal pain, headache, dizziness, peripheral neuropathy, stupor, seizures, brain damage, and impaired reflexes have been associated with dermal or oral exposure.²⁶ 2,4-D is a known endocrine disruptor and can block hormone distribution and cause glandular breakdown. 2,4-D causes indirect disruption of the mitochondrial transmembrane potential, inhibition of oxidative phosphorylation, and decreasing levels of ATP in mitochondria. It is expected that the mitochondrial marker tiglylglycine would be elevated with mitochondrial damage caused by this chemical. The mutagenicity of 2,4-D is due to homologous recombination, AG mutation, chromosome aberrations, sister chromatid exchange and DNA damage, and also an increase in the frequency of DNA strand breaks.²⁶

Benzene, xylene, styrene, MTBE, and ETBE are volatile chemicals that are all associated with gasoline usage. MTBE and ETBE are gasoline additives used as replacements for tetraethyllead to improve combustion. These chemicals, however, are water soluble and when they leak from underground storage tanks can follow underground water plumes and contaminate underground wells used for drinking water. For example, the municipal water supply of Santa Monica, California, was contaminated in this way. The water wells were shut down for more than 14 years due to contamination with methyl tert-butyl ether (MTBE), a now-banned gasoline additive that was leaking from gas stations in the area. When this happened, the city was forced to rely on imported water for 85% of its needs. In 2006, Santa Monica reached an agreement with three major oil companies responsible for the MTBE contamination to restore the contaminated wells so that they could once again be a viable drinking water source. The wells and new facilities at the Santa Monica Water Treatment Plant began producing potable water again on December 4, 2010.²⁷

Almost all chemicals can be reduced by eliminating the sources of contamination, by eating organic foods, drinking reverse osmosis purified water, and living in areas with low air pollution. Sauna treatment, especially sauna treatment using the Hubbard protocol, was especially useful in the treatment of rescue workers exposed to a variety of toxic chemicals in the September 11 terrorist attack in New York City.²⁸

Notes

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2. Environments and contaminants: chemicals in food [Web page]. United States Environmental Protection Agency. http://www2.epa.gov/ace/environments-and-contaminants-chemicals-food. Accessed October 5, 2015.

3. Rauh V, Arunajadai S, Horton M, et al. Seven-year neurodevelopmental scores and prenatal exposure to chlorpyrifos, a common agricultural pesticide. Environ Health Perspect. 119:2011;1189–1195.

4. Bourchard M, Chevrier J, Harley K, et al. Prenatal exposure to organophosphate pesticides and IQ in 7-year-old children. Environ Health Perspect. 119:1999;1189–1195.

5. Rauh V, Perera F, Horton M, et al. Brain anomalies in children exposed prenatally to a common organophosphate pesticide. Proc Natl Acad Sci USA. 2012;109:7871–7876.

6 Jokanovic M, Kosanovic M. Neurotoxic effects in patients poisoned with organophosphate pesticides. Environ Toxicol Pharmacol. 2010;29:195–201.

7.Salama M, El-Morsy D, El-Gamal M, et al. Mitochondrial complex I inhibition as a possible mechanism of chlorpyrifos induced neurotoxicity. Ann Neurosci. 2014;Jul;21(3):85–89.

8. Basha PM, Poojary A. Mitochondrial dysfunction in aging rat brain regions upon chlorpyrifos toxicity and disorders of soleucine cold stress: an interactive study. Cell Mol Neurobiol. 2014;Jul;34(5):737–756.

9. Bennett M, Powell J, Daniel J, et al. Tiglylglycine excreted in urine in metabolism and the respiratory chain measured by stable isotope dilution GC–MS. Clin Chem. 1994;40(10):1879–1883.

10. Windham G, Zhang L, Gunier R, et al. Autism spectrum disorders in relation to distribution of hazardous air pollutants in the San Francisco bay area. Environ Health Perspect. 2006;Sep;114(9):1438–1444.

11. Roberts E, English P, Grether J, et al. Maternal residence near agricultural pesticide applications and autism spectrum disorders among children in the California central valley. Environ Health Perspect. 2007;115(10):1482–1489.

12. Weissman J, Kelley R, Bauman M, et al. Mitochondrial disease in autism spectrum disorder patients: a cohort analysis. PLoS One. 2008;3(11) :e3815. doi:10.1371/journal.pone.0003815. Epub 2008 Nov 26.

13. Miller M, Radike M, Andringa A, et al. Mitochondrial changes in hepatocytes of rats chronically exposed to vinyl chloride and ethanol. Environ Res. 1982;Dec;29(2):272–279.

14. Poling J, Frye R, Shoffner J, et al. Developmental regression and mitochondrial dysfunction in a child With autism. J Child Neurol. 2006;February ;21(2):170–172.

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16. Wagoner J. Toxicity of vinyl chloride and poIy(vinyl chloride): a critical review. Environ Health Perspect. 1983;Vol. 52, pp. 61–66.

17. Agency for Toxic Substances and Disease Registry. Toxicological Profile for Pyrethrins and Pyrethroids [online document]. http://www.atsdr.cdc.gov/toxprofiles/tp155.pdf. Accessed October 12, 2015.

18. Müller-Mohnssen H, Hahn K. A new method for early detection of neurotoxic diseases exemplified by pyrethroid poisoning. Gesundheitswesen. 1995;Apr;57(4):214–222.

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21. The National Institute for Occupation Safety and Health. Updated June 2014. The effects of workplace hazards on male reproductive health [online publication]. http://www.cdc.gov/niosh/docs/96-132. Accessed October 8, 2015.

22. Burns C, Beard K, Cartmill J. Mortality in chemical workers potentially exposed to 2,4-dichlorophenoxyacetic acid (2,4-D) 1945-94:an update. Occup Environ Med. 2001;58:24–30.

23. Duffard R, Garcia G, Rosso S, et al. Central nervous system myelin deficit in rats exposed to 2,4-dichlorophenoxyacteic acid throughout lactation. Neurotoxicol Teratol. 1996;18:691–696.

24. Rosso S, Garcia G, Madariaga M, et al. 2,4-Dichlorophenoxyacetic acid in developing rats alters behaviour, myelination and regions brain gangliosides pattern. Neurotoxicology. 2001;21:155–163.

25. Bortolozzi A, Duffard R, Evangelista de Duffard A. Behavioral alterations induced in rats by a pre- and postnatal exposure to 2,4-dichlorophenoxyacetic acid. Neurotoxicol Teratol. 1999;21(4):451–465.

26. Bukowska B. Toxicity of 2,4-Dichlorophenoxyacetic acid– molecular mechanisms. Polish J Environ Stud. 2006;15(3):365–374.

27. Santa Monica water treatment plant [Web page]. Santa Monica Public Works. http://www.smgov.net/santamonicawatertreatmentplant.aspx. Accessed October 12, 2015.

28. Cecchini M, Root D, Rachunow J, et al. Chemical exposures at the World Trade Center: use of the Hubbard sauna detoxification regimen to improve the health status of New York City rescue workers exposed to toxicants. Townsend Lett. April 2006. Available at

http://www.townsendletter.com/Dec2006/chemexp1206.htm. Accessed October 13, 2015.