Most people would be surprised to learn how little of certain chemicals is required to produce quite pronounced effects in biological systems, including the human body. For example, depending on the chemical, our olfactory receptors which are involved in our sense of smell, may react to as little as one billionth of a gram. Treatment of cells derived from the human ovary with fractions of a billionth of a gram of the toxic pollutant dioxin has been shown to reduce the production of one of the female sex hormones.1 Around 2-3 micrograms (a microgram is a millionth of a gram) of vitamin B12 taken daily is enough to keep us from developing a form of anaemia, 5 micrograms are sufficient to prevent rickets (a bone disease) in children, and 10-20 micrograms of vitamin K are enough to prevent very young children from bleeding.
Conversely, people would also be surprised learn how little of certain poisons are required to cause illness. For example, one microgram or less of the botulism or tetanus toxins is sufficient to cause harm or even death. There are, as well, other more common examples of how small amounts of certain chemicals have the potential to cause harm or even death and these include the allergies to certain foods such as peanuts, egg or milk where a few milligrams (thousandths of a gram) are sufficient to cause a response.
There is therefore no question that amounts that we consider exceedingly tiny do have the potential to keep us healthy or even kill us. It all depends on the nature of the chemical and the various bodily processes it affects. So, while small can be beautiful, it can also be lethal.
There is also no doubt that some of the chemicals we are exposed to in our everyday lives are harmful to us if taken in large enough amounts. Indeed, one could argue that just about everything, even oxygen and ordinary salt are poisonous if the amounts taken are sufficiently large. Certainly, many of the pesticides, metals such as arsenic, lead and mercury, and a great number of the industrial waste products are considered toxic and yet governments believe that, in the amounts we are exposed to, they do not pose a risk to our health. However, there are numerous examples of chemicals causing disease when taken in amounts much lower than the poisonous dose.
Perhaps the best example is smoking. While there are dozens of potentially poisonous and cancer-causing substances in cigarette smoke, the amounts a smoker is exposed to in each cigarette are much lower than that required to harm. And yet research has demonstrated fairly clearly that there is a link between smoking and lung cancer in particular.
Another example is the toxic metal arsenic. In large doses, from a few hundred milligrams to gram amounts, it kills – the actual amount depending on the chemical form of the arsenic. But chronic exposure to amounts a hundred-fold or more lower than this can also cause skin abnormalities, nerve damage, and anaemia. This is clear from the poisoning that occurs through ingestion of arsenic contaminated groundwater in concentrations of as little as one tenth of a millionth of a gram per millilitre in some parts of the world e.g. Bangladesh.2
Similarly, while a few grams of mercury in its different forms can kill outright, chronic exposure to much smaller amounts may not kill but can affect the function of the brain, kidney and other organs as occurred in Minamata Bay in Japan through eating seafood contaminated with the metal.3
There is yet another factor which can profoundly influence the effect of a chemical and that is the timing of exposure. A good illustration of this is the drug thalidomide which was taken by many pregnant women in the late 1960s. In non-pregnant women the drug is relatively safe but in pregnant women as little as a single 50 mg dose (i.e. one twentieth of a gram) taken from 20-30 days after conception may be sufficient to cause devastating birth defects. What thalidomide taught us was that some chemicals – even in apparently non-toxic doses ‒ may be more toxic in humans than in some of the animal species used to test for toxicity. In the case of thalidomide, mice, often used for testing drugs, were much more resistant to its effects than other animals. And finally, the toxic dose can vary according to how a chemical enters the body i.e. through the skin, mouth, or the lungs.
The usual way of determining whether a chemical is potentially toxic is to try it out on animals, the most used species being rodents such as rats and mice. However, there are a number of problems with these sorts of studies. Firstly, rats and mice are not humans and, despite the fact that there are similarities in the way rats and humans handle chemicals such as polychlorinated biphenyls (PCBs), there are differences as well.
Secondly, most toxicology studies, particularly for environmental chemicals such as PCBs, do not involve very long-term chronic exposure which can more accurately mimic the exposure of humans. The situation is different with pharmaceuticals where toxicological testing is much more rigorous and, moreover, even after approval for a particular drug, once the drug is released into the market there is continuing monitoring. It is impractical to subject the thousands of industrial chemicals to this degree of testing and scrutiny.
Thirdly, the studies carried out with rodents do not take into account the fact that many humans have pre-existing conditions (diabetes, cancer, arthritis, hepatitis, nephritis etc), or smoke, drink excessively, have abnormal liver function, or take recreational or other drugs. It is further complicated because there is increasing evidence that there are genetic differences in the way we deal with chemicals such as drugs and pollutants. These factors can affect the capacity of an individual to deal with a chemical, perhaps even at the very low concentrations that may be present in our food, water or air.
And finally, it must be emphasised that any toxicological testing that is carried out, even for pharmaceuticals, almost always involves the testing of a single substance. It is rare that mixtures of chemicals are used. However, in the case of environmental chemicals, it is the rule rather than the exception that we are exposed to complex mixtures. Indeed, recent analyses of the exposome have shown that the human body may contain a great number of chemical pollutants which have accumulated throughout life.10 Despite what governments may tell us, there is no way one can know for certain what these complex mixtures may do to our health.
Whereas in the past toxicologists (scientists who study poisonous substances) believed that there was a concentration threshold below which poisons had no effects on animals or humans, scientists working in an area of toxicology known as "hormesis" have espoused the view that sub-lethal amounts of a poison may also produce some effect, perhaps even an opposite effect. Perhaps because this view smacks somewhat of homeopathy, an alternative way of treating disease and largely dismissed by many scientists. However, in the past decade there have been numerous reports in journals that point to measurable effects at very low and sublethal amounts of a toxic substance.
A few examples are worth noting. Cadmium is a known toxin and chronic exposure can lead to bone and kidney diseases. Acute exposure to cadmium leads to severe gastrointestinal problems and severe lung inflammation ultimately leading to death. One of the major effects of chronic exposure is damage to the kidneys. Experiments carried out with cadmium using lung cells taken from human embryos actually showed two effects – one at low concentrations that stimulates the growth of these cells, and an inhibition of cell growth at high concentrations.4
The effects of glyphosate provide another example because there is increasing evidence that in much smaller amounts, such as may occur in spray drift onto non-sprayed fields, it may stimulate growth of some plants.5 These examples, and there are many others, point to a phenomenon that is truly surprising. In the case of the examples cited, it indicates that very small amounts of something that is toxic may be beneficial. Of greater importance, however, is the conclusion that very small amounts of substances, both toxic and non-toxic, may not necessarily behave in a manner expected. And, further, if toxic substances may have certain beneficial effects at very low levels, can they also have other, as yet unrecognised, harmful effects? After all, in the examples cited, and in much of the available literature on the topic of hormesis, the focus has been on the systems known to be affected by large doses of a toxin without any consideration of the scores of other systems or pathways that may be vulnerable.
Another way that tiny amounts of chemicals can produce an effect is via the process of synergy where the combined activity of two separate substances is much greater than that predicted by adding the sum of each. This is a well-known phenomenon in medicine where mixtures of drugs can apparently produce unexpected, and often harmful, effects that are not predictable from a knowledge of the effects of each individual drug.
There are also many examples of synergy using mixtures of pesticides against insects or fungi. Perhaps the most impressive studies are those showing synergy between rotenone, an insecticide found in derris dust, and lipopolysaccharide (LPS), parts of the cell wall of many bacterial strains. LPS occurs naturally in humans because antibodies to LPS are routinely detected in blood and very small amounts, of the order of fractions of a millionth of a gram, can promote inflammation. Rotenone is a mitochondrial poison and works by stimulating the production of free radicals and this can damage the mitochondria, the tiny powerhouses of the cell, ultimately leading to the death of the cell.
A group of US researchers, studying the combined effects of rotenone and LPS on certain brain cells that specialise in the production of dopamine, an important substance involved in the transmission of nerve impulses in the brain, found that while rotenone, by itself, at concentrations much lower than the toxic dose, produces an apparently negligible effect on the brain cells, in combination with LPS (again at levels below that required to produce any direct effect), can induce a large increase in free radical formation ultimately leading to the death of cells.6 This is an interesting observation with relevance to Parkinson’s disease, a degenerative disease affecting humans, which is caused by a gradual loss of function of brain cells that make dopamine. The researchers speculated that while the causes of Parkinson’s disease are not known, it is possible that the disease may result from the effects of interactions among multiple factors, another way of saying that synergism may be involved.
There is yet another way tiny sub-lethal amounts of a substance can produce marked and unexpected effects and that is via a mechanism that is referred to as "priming". There is some overlap between the mechanisms of hormesis, synergy and priming. However, priming is a biological process that is well known to scientists, particularly those who work in the field of immunology.
Some of the special proteins produced by the immune system, the so-called cytokines, can interact with certain immune cells, to produce a cell that is "primed", that is the cell is sensitised and potentially hyperactive as compared to corresponding non-primed cells. A primed cell is ready to go and all it takes is some other substance to produce an effect. There are examples of pollutants, such as pesticides that, at non-toxic levels, can greatly augment the response of immune cells via priming. Studies carried out by a group of Italian scientists showed that chronic exposure rat immune cells to permethrin, a well-known pesticide, at levels not considered to be toxic, primes the cells and this results in a greatly amplified response to other stimuli.7
The cells studied by the researchers produce free radicals which can kill bacteria but, in excess, free radicals can also damage delicate tissue causing disease such as arthritis. The permethrin-primed response measured by the scientists was so great (more than 30 times greater than normal) that the researchers speculated that, if something similar occurred in humans, then chronic exposure to some pesticides had the potential to harm.
A similar augmentation of an immune response has also been shown in laboratory mice.8 In this case the mice had been previously primed with albumin, a protein found in blood, which had rendered their lungs very sensitive (a type of priming). Motorcycle exhaust particles, known to contain a variety of pollutants with the capacity to induce a type of lung inflammation, were introduced into the lungs of both sensitised and non-sensitised animals and the response to these treatments was measured. The researchers concluded that prior sensitisation and subsequent treatment with a mixture of environmental pollutants greatly augmented inflammatory processes in the lung. This is especially relevant to people with asthma, whose airways are particularly sensitive.
The bottom line
We may need to re-evaluate our beliefs on toxicity because they are often based on animal studies that do not take into account the differences between animals and humans, the fact that much of our exposure can occur over many years, and there are likely to be genetic differences in our abilities to handle chemical pollutants. There is increasing evidence that exposure to tiny amounts of a toxic chemical may have unexpected effects through the process of hormesis, or through synergism or priming which depend on the combined actions of a pollutant with other substances that may be present in our blood and tissues. Some of the pollutants we are exposed to have been demonstrated to produce effects via these processes in animal, and even human, tissues such as the brain and the immune system.
However, there are literally thousands of chemical reactions occurring in our bodies at any time and it is likely that at least some of these reactions are either inhibited or stimulated in the presence of small amounts of one or more of the many pollutants taken up into our bodies, possibly affecting the function of the organ(s) in which the reactions are taking place.
Alfred Poulos' new book 'The Secret Life of Chemicals' is available from the author: [email protected]
- Baldridge MG et al (2015). Very low-dose (femtomolar) 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) disrupts steroidogenic enzyme mRNAs and steroid secretion by human luteinizing granulosa cells. Reproduct Toxicol 52, 57-61.
- Argos M et al (2011) A prospective study of arsenic exposure from drinking water and incidence of skin lesions in Bangladesh. Am J Epidemiol 174, 185-194.
- Harada M (1995) Minamata disease: methylmercury poisoning in Japan caused by environmental pollution. Crit Rev Toxicol 25, 1-24
- Jiang G et al (2009). Biphasic effect of cadmium on cell proliferation in human embryo lung fibroblast cells and its molecular mechanism. Toxicol In Vitro 23, 973-979.
- Velini ED et al (2008). Glyphosate applied at low doses can stimulate plant growth. Pest Manag Sci 64, 489-496.
- Gao HM et al (2003) Synergistic dopaminergic neurotoxicity of the pesticide rotenone and inflammogen lipopolysaccharide: relevance to the etiology of Parkinson’s disease. J Neurosci 23, 1228-1236.
- Gabienelli et al (2009). Effect of permethrin insecticide on rat polymorphonuclear neutrophils. Chem Biol Interact 182, 245-252.
- Lee CC et al (2008). Motorcycle exhaust particles augment antigen-induced airway inflammation in BALB/c mice. J Toxicol Environ Health A 71, 405-412.
Published in Chain Reaction #134, December 2018. National magazine of Friends of the Earth Australia. www.foe.org.au/chain_reaction
Book Review: The Secret Life of Chemicals
The Secret Life of Chemicals
By Prof. Alfred Poulos
Order from https://professoralfredpoulos.com/
Review by Anthony Amis
In his second book, Prof. Alfred Poulos investigates 'The Secret Life of Chemicals', offering a detailed and mind-boggling overview about how chemical pollutants interact with human beings and how they can impact on health. Prof. Poulos has worked in universities, research institutes and hospitals in the UK, USA, Canada and Australia. He held the position of Chief Medical Scientist at the Women's and Children's Hospital in Adelaide, South Australia for many years; has a professorship from Adelaide University, for his research into genetic diseases, fats and fat metabolism; and has published over 150 papers in international scientific and medical journals.
As a follow-up to the 2005 publication 'The Silent Threat' (reviewed in Chain Reaction #133), this offering is more detailed and equally impressive. Taking three years to write, Poulos has the ability to examine extremely complex processes and explain them in ways that people without training in this field can comprehend.
With the internet saturated with information about the dangers of a myriad of substances, Poulos acts as a guide for the reader attempting to come to grips with the often contradictory positions of published science and "junk science".
Not only does the book outline some of the most troublesome chemicals in terms of human health, but the author also explains the latest scientific thinking into how a host of chemicals impact on the body.
I particularly found the chapters on genetic variability and the risk of disease particularly useful as this area appears to be of great significance to explaining why one person may become ill from exposure to a chemical, whilst another person exposed to the same chemical may not have any adverse reaction at all. This conundrum makes regulating chemicals extremely difficult, particularly in terms of defining what a safe dose actually is.
I also appreciated the chapters of environmental chemicals and our genes, mitochondria and immune system, all of which were very insightful. It is also encouraging to see a chapter on "Just because the amounts are small, does that mean they are safe?". This has been an increasingly topical area in regards to a host of pesticide issues that I have been researching and again has implications regarding how what may be OK for one person can be devastating for someone else.
Drawing from the latest peer-reviewed medical and scientific literature (with over 600 references), the book includes chapters on:
- The health effects of plastic packaging
- Pesticides in our food
- Toxic metals such as lead, arsenic, mercury and how they have ended up in the food chain.
- Air pollutants and their presence in home, through sprays, detergents and cleaning agents
- Plastics in the ocean and in landfill and the chemicals they release
- 'Indestructibles' – the industrial chemicals like PCBs, dioxins and PBDE flame retardants that hang around and don't break down very easily
- Non-stick chemicals added to our cooking utensils
- Chemical exposure in our workplaces
- Effects of environmental chemicals on our genes and immune systems
Prof. Poulos says that the book was inspired by a wish for his grand-children grow up in a less polluted world. "You think of the legacy you are leaving them: What sort of planet are you bequeathing for them? You don't just sit back and think there's nothing you can do – no matter what age you are."
For anyone campaigning on toxic issues, from pesticides, to air pollution, plastics, fluorocarbons, radiation and chemical exposure in the workplace, "The Secret Life of Chemicals" should be mandatory reading.
Published in Chain Reaction #134, December 2018. National magazine of Friends of the Earth Australia. www.foe.org.au/chain_reaction