How do we normally detox xenobiotics?

For chemicals and xenobiotics to be excreted outside of the body, they need to undergo certain transformation processes known as biotransformation. Classically, these processes are divided into three phases: functionalization, conjugation, and excretion:

Phase I

Oxidation

Reduction

Hydrolysis

Phase II

Conjugation

Excretion

Phase 1 – Functionalization:

In this phase chemicals are either neutralized or converted into a more or less potent form of the compound, which prepares it to undergo conjugation in phase 2, and eventually to be fully excreted. The main three reactions that occur during this phase is oxidation, reduction or hydrolysis by attaching a function group (-OH or -O) to these compounds and consequently make them more water soluble. The fate of these metabolites is either to undergo further phase 1 process, moved into other parts of the body for use, shunned outside of the body via bile, or are redirected into phase 2 for further conjugation.

Phase 2 – Conjugation:

This phase of the biotransformation process transforms metabolites into a more polar form by adding an acetyl, methyl, a sulfur compound, some amino acids, glutathione or glucuronate. The addition of these compounds render them ready for elimination. Conjugation enzymatic processes typically require energy in the form of ATP. Main conjugatory reactions that happen in phase 2 include:

- Acetylation

- AA conjugation with Glycine, Taurine or Glutamine

- Glucuronidation

- Glutathione conjugation

- Methylation

- Sulfur conjugation

Phase 3 – Excretion:

After they go through phase 1 and phase 2 of biotransformation, xenobiotics are then ready to be excreted outside of the body either via urine (renal route) or via stool/bile (intestinal route). Chemical compounds are transported across (in and out) the cell membrane via protein pumps. Two types of transporter are available to handle these chemicals, the ABC transporters move the chemicals outside of the cell, while organic anion transporters move chemicals in the cells. Subtypes of ABC transporters are the MRP proteins 1 to 5 (GSH-dependent multidrug resistant proteins). MRPs are polymorphic and overexpression of these proteins can lead to drug resistance, that’s why the primary location of MRPs are in the liver, kidney and small/large intestine. These transporters are GSH dependent, and depletion of GSH can slow down the action of MRPs, and GSH repletion improves their function. That is how N-acetyl Cysteine enhances the excretion of methylmercury via renal MRPs. Presence of conjugated chemicals (which are primarily lipophilic) in bile or kidney tubules presents a potential for these chemicals to be reabsorbed via ABC transporters, leading to hepatic recirculation.

What happens in people with MCS?

Genetic predisposition:

Research shows an important tie between MCS and certain genes responsible for detoxification of environmental chemicals. A significantly impaired ability to process these compounds effectively could explain why only low levels are required to produce symptoms. One study revealed that Caucasian women were 3.36 times more likely to have MCS if they had a certain mutation of a major detoxification gene called CYP2D6. Among those who also had a certain mutation of a second detox gene, NAT2, they were 18.7 times more likely to have MCS than controls. These two genes interact with each other to coordinate the process of biotransformation, and if both are mutated in a certain way then it is not surprising that symptoms could result. Interestingly, the PON-1 gene mutation associated with neurological symptoms of Gulf War Syndrome also contributes to a higher propensity toward having MCS. Gulf War Syndrome is characterised by chronic fatigue, headaches, insomnia, memory problems and other symptoms that overlap with MCS. Other genes that could contribute include those responsible for availability of glutathione, the body’s master antioxidant and stabilizer of toxins. Mutations of the GST or GPX genes inhibit glutathione availability, so you lose the protective effect of glutathione which keeps toxins and chemicals from triggering an immune reaction.

Psychogenic impact:

MCS is correlated with depression and other psychological illnesses. The psychological distress experienced by MCS patients, many of whom make life-altering changes to reduce their exposure, is undeniable. The question is whether this is a cause or result of the primary disease. The clinical ecologists tend to argue the latter, while conventional medicine considers MCS to be mainly psychogenic in origin. One theory is that it is related to operant conditioning and a self-fulfilling prophecy. This means the more someone believes that a chemical is toxic and going to cause a symptom, then every time they are exposed to it and experience a symptom, whether it was caused by that exposure or not, that association becomes stronger. The nocebo effect is the negative version of placebo effect, in which, after being told about the negative side effects of a medication, one is more likely to experience those side effects. Research suggests this may play a role in at least certain forms of MCS.

One study on IEI-EMF (a form of MCS specific to EMF exposure) divided people into two groups, one of which watched a film about the adverse effects of EMF exposure, and others a control film. The experimental film increased the likelihood of experiencing symptoms akin to those mentioned in the report after receiving sham EMF exposure. Watching the film also increased the likelihood of attributing the symptoms to the sham exposure among those with high anxiety, as well as the likelihood of believing themselves to be sensitive to EMF. A similar study, though of a smaller sample size, showed similar results of a nocebo response elicited by alarmist reports emphasizing adverse effects of EMF. Healthy participants who viewed the alarmist video had a significant increase in symptoms, state anxiety and risk perception relative to the control group. Another study showed that belief of exposure strongly predicted symptom severity. No correlation was found between EMFexposure and MCS symptoms, and no significant difference in symptom severity or exposure detection was found between participants.

Neurogenic theory:

One theory behind multiple chemical sensitivities is what is known as the Limbic System theory. Patients with MCS are noted to have psychological and psychiatric abnormalities such as addictions, violence, binging and hypersexual activity. To explain such behavioral changes, a model that involves the hypothalamus, and the olfactory system in particular, was explored. Being a part of the hypothalamus, the olfactory and limbic system attracted a lot of attention and consideration as a focal point where immune, endocrine and nervous systems all interact. This led to the speculation that adverse reactions to foods and chemicals can be explained with the neuronal circuitry of the limbic system.

References:

(McKeown-Eyssen G, Baines C, Cole DE, Riley N, Tyndale RF, Marshall L, Jazmaji V. Case-control study of genotypes in multiple chemical sensitivity: CYP2D6, NAT1, NAT2, PON1, PON2 and MTHFR. Int J Epidemiol. 2004 Oct;33(5):971-8. doi: 10.1093/ije/dyh251. Epub 2004 Jul 15. PMID: 15256524.)

Witthöft M, Rubin GJ. Are media warnings about the adverse health effects of modern life self-fulfilling? An experimental study on idiopathic environmental intolerance attributed to electromagnetic fields (IEI-EMF). J Psychosom Res. 2013 Mar;74(3):206-12. doi: 10.1016/j.jpsychores.2012.12.002. Epub 2012 Dec 23. PMID: 23438710.

Verrender A, Loughran SP, Anderson V, Hillert L, Rubin GJ, Oftedal G, Croft RJ. IEI-EMF provocation case studies: A novel approach to testing sensitive individuals. Bioelectromagnetics. 2018 Feb;39(2):132-143. doi: 10.1002/bem.22095. Epub 2017 Nov 10. PMID: 29125197.

Verrender A, Loughran SP, Dalecki A, Freudenstein F, Croft RJ. Can explicit suggestions about the harmfulness of EMF exposure exacerbate a nocebo response in healthy controls? Environ Res. 2018 Oct;166:409-417. doi: 10.1016/j.envres.2018.06.032. Epub 2018 Jun 21. PMID: 29936289.