Title: Synergistic Effects of Chemical Mixtures

Key words: carcinogenic, mutagenic, toxicology, combinations, synergy, chlordane, accumulation, breast milk, hormones, hormone disrupters, detergents, plastics, pesticides, risk assessment, biosphere, phylogenetics, organochlorine compounds, cancer, homeostasis

Date: Oct 2000

Category: 15. Materia Medica

Type: Article

Author: Dr V Howard in The Ecologist Vol 27, No 5, Sept/Oct 1997



Synergistic Effects of Chemical Mixtures

Can We Rely on Traditional Toxicology?

Recent research has shown that the synergistic effects among chemicals used in different combinations are much more dramatic than was previously thought. Yet we continue to test chemicals for their possible carcinogenic or mutagenic potential in isolation from each other. This procedure can no longer be justified.


To determine their real effect, we need to test chemicals in all their possible combinations, which is both logistically and financially impossible. As the author has pointed out, "to test just the commonest 1,000 toxic chemicals in combinations of three (at a standardised dosage) would require at least 166 million different experiments".  Can we solve the problem other than by dramatically reducing the number of chemicals to which we are exposed?

Classical toxicology approaches the study of chemical substances one at a time. The incidence of a given toxic effect can be plotted against dosage to construct a dose response curve. From such a curve it is sometimes possible to decide if there is a safe level of exposure to a particular chemical. Now there is a new problem. We have in our bodies today what has been estimated to be between 300 and 500 chemicals that simply would not have been there 50 years ago, because at that time they did not exist or were present in the environment at undetectable levels. Trying to work out the toxicology of such a complex mixture presents many problems and renders the classical approach (of examining chemicals one at a time) quite useless.


The chemical industry received some bad news last June. Science magazine published a new study showing that some combinations of hormone-disrupting chemicals are much more powerful than any of the individual chemicals by themselves1. Science magazine is the conservative voice of American mainstream scientific thought in the USA. Until then Science had largely ignored the possibility that industrial chemicals may be interfering with hormones in wildlife and humans. The study showed that combinations of two or three common pesticides at low levels that might be found in the environment can be between 160 and 1,600 times as powerful as any of the individual pesticides by themselves. It further demonstrated that one chemical, chlordane, which has no ability to disrupt hormones by itself nevertheless greatly magnified the ability of other chemicals to disrupt hormones.


That paper has now been formally withdrawn by the authors because it has not been possible to reproduce the results, a step which is to be applauded as an act of scientific honesty. However, the danger is that there will be a tendency by some to say that synergism between chemical pollutants is no longer a problem. Nothing could be further from the truth. There are a number of studies from different labs indicating, for example, synergistic enhancements of mixtures of up to 10 times the individual effects2.  The environmental protection apparatus of the UK and, indeed, the world, is at present based on studies of individual chemicals acting alone.


It is worth noting that nature has assiduously avoided evolving the capability to synthesise certain groups of chemical compounds. For example, in the whole of vertebrate phylogeny, there have been no chemical pathways developed for the synthesis of higher chlorinated or perchlorinated organic molecules. The fact that a few plant species can produce, for example, organo-chlorines, mainly as self-protective biocides, tells us that nature would have been perfectly capable of evolving this chemistry in the mainstream of animal evolution. The fact that it didn't should warn us that their introduction into the body is likely to be damaging!


We now see a global distillation of such chemicals as a result of bulk production by the chemical industry. These compounds, which are persistent and fat-soluble, accumulate in the body as life progresses and can be passed on to the next generation across the placenta and in breast milk. It should not surprise any to learn that these chemicals have untoward effects. If the biosphere is flooded with organic molecules that nature has specifically eschewed, then harm will almost inevitably follow, particularly when many of them are designed to be toxic - for example, pesticides.


Hormones are natural chemicals that act as messengers, possibly unique travelling through the blood-stream, regulating various bodily processes, co-ordinating the body's activities to maintain health.  Hormones are particularly important during growth and development - an egg, an embryo, a foetus, an infant.  About 100 different hormones have now been identified, and they control growth, development and behaviour in all vertebrates (fish, birds, reptiles, amphibians and mammals), including humans.  Disrupters of the endocrine system are not like most toxins. With the latter, there is usually a concentration below which the toxic effect cannot be detected.  The endocrine system can be likened to a running motor, which is set at an equilibrium that has taken many millennia to evolve and stabilise.  Any disrupting influence can only 'up regulate' or 'down regulate' the system and thus there will not be a 'zero effect' dose level.


Since 1991, studies have shown that at least 50 synthetic industrial chemicals can interfere with hormones and disrupt normal growth and development in birds, fish, mammals, reptiles, amphibians and humans4. The results of such interference can include changes in sexual preference and behaviour, reduced gonad size, diminished sperm count, various cancers, nervous system disorders, birth defects and damage to the immune system among other effects. Many of the 50 hormone disrupting chemicals are commonly found in detergents, plastics and pesticides. In response to these studies, the chemical industry has asserted that low level environmental exposures are not powerful enough to affect humans5.


The idea that common industrial chemicals may be interfering with the hormones of wildlife and humans has far-reaching implications. If it is true it means that the chemical industry, as we know it, poses a threat to a great many forms of life on Earth and the majority of higher animals. How can we learn whether this is true?


Chemicals with vastly different molecular structures have proven to be hormone disrupters6. This means that a chemical’s ability to disrupt hormones cannot be discovered simply by examining a diagram of the molecule and therefore the study of so-called structure/function relationships is not helpful. Thus, thousands of chemicals will need to be tested individually for their ability to disrupt hormones. A thorough battery of tests has not yet been devised and there are now 70,000 chemicals currently in commercial use, with about 1,000 new ones added each year. The prospect of testing the toxicity of this number of chemicals, even individually, is daunting. No one knows where the resources would come from to conduct such a large number of tests.


If scientists have to study combinations of chemicals, their job is vastly increased. For example, the 166 million different experiments needed to test just the commonest 1,000 toxic chemicals in unique combinations of three (and this disregards the need to study varying doses). Even if each took just one hour to complete and 100 laboratories worked round the clock, seven days a week it would still take over 180 years to complete such a test!


This is not the first evidence that some combinations of chemicals are more powerful than any of their individual chemicals. Earlier in 1996 researchers at the Duke University Medical Centre published a study of three chemicals to which US soldiers were exposed during the Gulf War. None of the three chemicals by itself caused nerve damage in laboratory animals but together the three chemicals showed powerful nerve-damaging effects9.


Even earlier, studies had shown that exposure to radiation enhances the toxicity of certain chemicals10 and that tobacco smoke and asbestos enhance each other's toxicity11.  No routine toxicological tests of chemical combinations to assess chemical dangers are performed however.  Nor are they required by regulatory bodies. For example, the US National Research Council (NRC) recently studied the problem of doing 'risk assessments' for combinations of chemicals. The NRC concluded that simply adding up the individual toxicity was the way to handle combinations. NRC said this approach would underestimate the toxicity of combinations of chemicals no more than 10-fold12, an approach supported by the Health and Safety Executive. To date, no studies have looked at more than about five chemicals in mixtures for the demonstration. However, we have hundreds of xeno-chemicals in our bodies and the levels of synergism possible within such complex mixtures remain unknown.


Yet more worrying is the concept that, if these chemicals can potentiate each other then they may be able to potentiate our own naturally occurring endogenous oestrogens or phytoestrogens (plant oestrogens) which occur naturally in bulk in the diet. This hypothesis has yet to be tested preferably on the in vivo models that a number of scientists (including this one) are working on. However, if synergism between xenoestrogens and natural oestrogens were shown to be a fact, then it could provide an explanation for much of what is being observed in human and wildlife populations and at relatively low levels of potentiation.


It is hard to imagine a practical, manageable testing programme that can sort through these problems and produce reliable, comprehensive results in less than a century. By that time, if damage is being done now, as many scientists believe is the case, it will be far too late. At the present time, we only have precaution to rely upon.


Risk Assessment - an example to illustrate the inadequacy of the approach

For a risk assessment to be meaningful, there must be a full understanding of all the factors involved. For building a structure like a bridge, for example, it can be seen that the majority of factors involved can be accounted for. However, with something as complex as the environment coupled with human health, to assume that everything is understood is as unrealistic as it is arrogant. Therefore, model assumptions have to be substituted for imponderables. Any risk assessment is only as good as its assumptions. As these can rarely if ever be verified, the public is offered 'fact-free' models in risk assessments, which can be used to prove literally anything. They are then dressed up in a highly technical language, which makes them incomprehensible to all but a few 'experts' and offered as reassurance that all is well.


When regulations for public protection from industrial air pollution were first drafted, they were concerned with acute exposure to irritant chemicals. The method was to observe clinical effects, such as acute respiratory distress, referral rates to hospital, prescription rates for various medicines as indices of the sensitivity of local receptors to a number of measured levels of known irritant pollutants.


Initially this approach was applied to coal-based products of combustion, mainly with respect to the oxides of sulphur. With the passage of time and the increasing use of oil products and various combustion processes, the emphasis has moved to consider the oxides of nitrogen and ozone, as well as sulphur oxides. The above-mentioned irritants have the common properties that they are transient in the environment and do not accumulate in the body. As the ambient level in the environment rises and falls so the levels in the bodies of those exposed mirrors these movements.


The following is an extract from ‘The Great U-Turn’ by Edward Goldsmith, Green Books, Ford House, Hartland, Bideford, Devon, UK.


Why Man-made Chemicals must be regarded as guilty until proven innocent

It took several thousand million years of evolution for the biosphere or world of living things, of which we are an integral part, to take on the shape industrial society found it in, and thereby provide an ideal habitat for humans and the myriads of other forms of life that compose it. During the course of this evolution, as Barry Commoner puts it: "The chemical, physical and biological properties of the Earth's surface gradually achieved a state of dynamic equilibrium, characterised by processes which link together the living and non-living constituents of the environment. Thus were formed the great elementary cycles that govern the movement of carbon, oxygen and nitrogen in the environment, each cycle being elaborately branched to form an intricate fabric of ecological interactions. In this dynamic balance, the chemical capabilities of living things are crucial, for they provide the driving force for the ecological cycles; it is the chemistry of photosynthesis in green plants, for example, which converts the sun's energy to food, fibre and fuel."  


The biosphere can function as a self-regulating natural system and maintain its basic structure, on which the very survival of its living components depends, only if the critical interrelationships between all its components - at all levels of organisation, including that of the atom or the molecule - are maintained.   As Commoner further points out "...the chemical processes which are mediated by the biochemical system represent an exceedingly small fraction of the reactions that are possible among the chemical constituents of living cells. This principle explains the frequency with which synthetic substances that do not occur in natural biological systems... turn out to be toxic."  


Commoner illustrates this principle thus:  

(a) Of the approximately one hundred chemical elements which occur in the materials of the Earth's surface, less than twenty appear to participate in biochemical processes, although some of those which are excluded, such as mercury or lead, can in fact react quite readily with natural constituents.

(b) Although oxygen and nitrogen atoms are common in the organic compounds found in living systems, biochemical constituents who include chemical grouping in which nitrogen and oxygen atoms are linked to each other are very rare. Although the numerous organic compounds that occur in biochemical systems are readily chlorinated by appropriate artificial reactions, and the chloride ion is quite common in these systems, chlorinated derivatives are extremely rare in natural biochemical systems. 

(c) It is no coincidence that these chemicals are not found in living tissues. There is good reason for it. The organisation that is the biosphere, has been able to evolve at the expense of eliminating possible reactions between these substances and living things. If any living systems once included them, then they have been eliminated by natural selection. The consistent absence of a chemical constituent from natural biological systems is an extraordinarily meaningful fact. It can be regarded as prima facie evidence that, with a considerable probability, the substance may be incompatible with the successful operation of the elaborately evolved, exceedingly complex network of reactions that constitutes the biochemical systems of living things. Furthermore, such theoretical considerations can be confirmed empirically. Thus, mercury is one of those eighty elements not essential for living processes. There is at least one good reason for this. Biochemical systems have evolved a system of enzymatic catalysis in which sulphur-containing groups play a crucial role. These react with mercury introduced into a living system, and enzymes are inactivated, often with fatal results.


There is also a good reason why synthetic nitroso compounds in which nitrogen and oxygen atoms are linked do not occur either in living tissue: they appear to interfere with the reactions involved in the orderly development of cells, and give rise to cancer and mutations. There is also a good reason why synthetic organochlorine compounds such as DDT and PCBs are excluded from living tissue. They are often very toxic or produce long-term damage such as cancer.


How does a living system succeed in excluding unwanted chemicals?  The answer is that either these chemicals are not present in its environment in that form which would permit them to interfere with it, or the system develops subtle homeostatic mechanisms for maintaining low levels within it, even if the levels outside are higher. These mechanisms, however, have developed via the evolutionary process - hence very slowly. They can only deal with chemicals found in that form and at that level to which the system was exposed during its evolutionary experience. In general the more the environment changes as a result of human activities, the less does it resemble that in which we evolved, and the less efficiently can our normal behavioural mechanisms enable us to adapt to it. Thus, while the human liver is capable of detoxifying those chemicals that it has learnt to detoxify over millions of years of human evolution, it is incapable of detoxifying chemicals to which it has not been exposed during this period.


These considerations led Professor Stephen Boyden of the Australian National University to formulate his principle of phylogenetic maladjustment. He pointed out that since the evolutionary process is adaptive, it must be when subjected to that environment with which we have co-evolved that our biological needs are best satisfied. This means that any modification of our environment causing it to divert from that to which we have been adapted by our evolution must lead to phylogenetic or evolutionary maladjustments and the greater this diversion the greater these maladjustments must be.