Rachel's Democracy and Health News #999, February 19, 2009

THE DAWNING AGE OF BIOCHEMISTRY REVEALS SEVERITY OF CHEMICAL RISKS

[Editor's introduction: The relatively new field of study called biochemistry tells us why industrial poisins are almost certain to cause harm whenever they enter living things.]

By Tony Tweedale

[Tony Tweedale runs a consultancy (R.I.S.K. -- Rebutting Industry's Science Through Knowledge) in Edinburgh, U.K. for toxics activists and scientists short on time, finding the most relevant toxicology results. tony.tweedale@phonecoop.coop]

Science advances largely when its analytical techniques do; in biology this has lead to biochemistry. Mankind has just begun to figure out the intricate sequences of chemical reactions that constitute life. Immediately this investigation shows that life's complexity, and its often tiny chemical signaling concentrations, shout out the message "Danger -- Take Care!" about bringing agents foreign to evolution into the web of life.

Life is an evolved system -- adaptable, but reliant on ultra- specialized biochemical systems. It is an aqueous (cells and organisms are like swamps), pressurized (space, the atmosphere and the ocean are a density continuum), photon-powered system; where the electrical charges arising from the atoms and the shapes of molecules (physics) trigger a torrent of subtle reactions (chemistry), which somehow became and remains organized as life (biology). Powered by cascades of energy originating as photons, cells perform at least hundreds of thousands of reactions every second.[1] The energy-releasing reactions that respiring cells use for energy proceed perpetually at even more astounding rates: 10 million ATP energy-containing molecules are created per second per admittedly-large muscle cell.[2] The enzyme catalase can turn 40 million molecules of hydrogen peroxide into water per second, its turnover rate.[3] But cellular reactions are not just fast, they are complex -- there are thousands of biology functions to be coordinated even in a single-cell organism, the cell may be part of an organ, and all organisms must coordinate a lot with their environment. Such complexity occurs in each of a large majority of the cells on the planet, of which one human has about 60 trillion.[4] Moreover, logic says that such busy reactions can only coordinate if they use low-level signals (or most of a human's thousands of signals would risk being drowned in noise). Biologists have created a new specialty called "signal transduction" and already it has thousands of studies that show biochemical reactions typically do proceed on low dose signals -- sometimes vanishing-ly low indeed (see e.g. the journal Science's signal transduction online collection[5]). Finally, even the fairly new advance in heredity -- genetics (which regulates all of life), the "one gene codes for (is the blueprint for) one protein" paradigm, has already been shown to be uselessly simple -- do a web search on "epigenetics."

Why would such a hyper-complex life system, evolved far along increasingly specialized paths, not be harmed by external influences? Mankind has assumed the opposite by thoughtlessly pouring into this subtle system a lot of chemicals and energy.

The Basis Of Toxicity

Recognizing the risks of that behavior begins with understanding that the properties of toxic chemicals are the same ones that determine the behavior of all elements. Reactions of atoms and molecules are caused by the strength of charges of atoms' electrons (influenced by the nucleus' protons and neutrons). A useful rule with which to predict reactivity is: "like is attracted to (dissolves in) like". Organic (carbon-based) molecules -- soil, vegetation, oil/fat, etc. -- carry few electronic charges; a pure hydrocarbon is quite neutrally- charged; such hydrocarbon-soluble molecules congregate by not repelling each other, and their lack of charge tends to make them un- reactive -- stable, persistent. Conversely, atoms and molecules that carry significant positive (less or further-distant from the nucleus electrons) or negative (more or more proximate electrons) charges are attracted to atoms of the opposite charge. They congregate in (are highly soluble in) water, as water has uniquely strong and opposing charges. Therefore reactive atoms and molecules are very mobile, but tend not to persist. Although life is an aqueous swamp and uses a lot of reactive atoms and molecules, its molecules are carbon based, so charge neutrality is also part of the biosphere. "Like is attracted to like" is very general rule, but incredibly useful for activists who need to predict roughly the behavior in the environment and in organisms to successfully prevent the trespass of a chemical.

Considering toxicity then: first, chemicals that are most reactive are toxic per se to life's molecules: being more water soluble, they are easily brought close to an opposing charge on life's molecules, reacting and doing damage to cells and their signals. But usually they lose their dangerous reactivity in their reaction. Reactive oxygen species (ROS) and other very reactive agents are frequently generated as the result of both foreign and natural agents interacting with life.[6] Another reason for the ubiquity of reactive damage is that ROS are used by life -- an activated immune system produces many ROS in its effort to get rid of microbial and chemical foreign agents. The activation of the immune system is today called inflammation- epinomyously: "rubor (redness), dolor, calor et tumor (swelling)", as the Roman physician Celsus saw it in the year 40. Health requires keeping the immune system in a close balance between immune deficiency and autoimmunity.[7] Inflammation is involved in many diseases, I suspect in all; and it is likely that so are reactive chemicals damaging all life, sometimes beyond our evolved resistance to and repair of reactive agent damage.

Second, for those "fat-soluble" elements and molecules which are toxic: they are more neutrally charged-relatively un-reactive other than being attracted to similar neutral molecules such as life's fat, where they accumulate. If they come into close proximity to life, there is a good chance their proximity will disrupt the delicate web of electronic charges used to create the biologic signals that are life; especially if the toxic molecules are not known to life. Unfortunately, these toxics do not easily react into an un-reactive state, nor do they leave proximity to life easily! We call these toxins persistent bio-accumulating toxins (PBTs) and these characteristics make them serious toxics indeed.

The halogen elements bond strongly to carbon, the skeleton of life, in the order: Fluorine > Chlorine > Bromine > Iodine.[8] Mankind wastes large amounts of energy to do this synthetically, and has created -- inside of our delicate biosphere -- millions of tons of halogenated organics, which because of that ability to bond strongly to carbon, tend to be PBTs. Only a few organo-halogens are used by life,[9] presumably because in most circumstances, life is too efficient to bother supplying the many enzymes that would be required to react such strong bonds. Note that the least strong of these bonds, C to Iodine, is the most widely used in biology, e.g. in the important thyroid hormone system. Thus our so useful halogenated solvents; chlorinated and fluorinated pesticides, brominated fire retardants and fluorinated non-stick coatings are almost always horrifically foreign to life -- hard for nature to destroy, accumulating in fat and concentrating up the food chains. As with all toxics, not being molded to life's purposes, they disrupt life's molecules and signals.

Also, we are so ubiquitously exposed to perhaps a couple dozen very high production volume non-PBTs toxics, that nevertheless they too are found in significant concentrations in us all the time: three- quarters of the 23 pesticides detected the general population of the USA were non-persistent ones, such as the herbicide 2,4-D.[10] The horrific poison plastic monomer bisPhenol-A (bPA, which can disrupt cells in 30 seconds, at parts-per-quadrillion concentrations) is not a PBT;[11] nor is the dioxin-saturated anti-microbial triclosan, a toxin found in most brands of intimate-contact consumer products.

Metals do not degrade and can also be foreign to life; some are PBTs, as lead and mercury, others as arsenic are not. Obviously, life makes much use of metals (at the core of many proteins, their electric charges are key to determining the shape of a protein, thus the protein's function; proteins create the signals that are the hallmark of life). But metals-the above, cadmium, berylium, aluminum, etc. -- appear to have other properties that are too extreme to be used in the biochemistry of life, as tens of them are very well established potent toxins, especially to the nervous system;[12] and US federal health agencies rank metals as posing the most risk to people of toxins in the environment[13] (probably only because mankind has used and studied them for longer than for organic chemicals). Simple changes in the electron shells of metals cause big differences in their bonding behavior (i.e. in their reactivity, solubility, and uptake); allowing additive, synergistic and antagonistic behaviors and toxic effects.[14]

Proving that an Agent Causes Harm

For all synthetic agents, well over a million published (which includes peer-review) studies have examined this strong hypothesis -- that agents foreign to the reactions constituting life will be toxic to life. As many studies again document the environmental fate and the exposure of organisms to these agents. After filtering out financial conflict of interests (the only one of a researcher's biases that is readily quantifiable) and based on a large random sample (n = 20,000+), I have discovered that almost 99% of the financially un- conflicted toxicology papers find risk.

It is important to understand the logic that although a research finding of risk is much more attractive to a journal editor than a finding of safety (one type "publication bias" -- but another is papers accepted by industry-associated journals), even a single valid finding of risk in the face of any number of findings of safety is cause for caution, while the reverse is not true. In fact, for each of the thousands high-volume chemicals marketed for years -- the time needed for academic toxicologists (who are still largely independent of industry's money) to study them -- we already have from a few to hundreds of published findings of risk. In short, a large majority of all independent published toxicology studies indicates that these toxic agents are destroying the subtle web of life.

However, proving causation is a tough task -- theoretically, nothing is ultimately provable until everything in the universe is known! Practically, proving causation is a stool supported by three legs: controlled animal experiments, epidemiology (correlations between exposure and disease in populations) and etiology (showing the individual steps that lead from the presence of agent A to disease outcome B) categories of evidence. Epidemiology typically studies humans, not other species, while we do not do controlled experiments on humans (except for a few very self- interested companies). Thus to practically prove causation, positive results in all three categories are needed and a "weight of the evidence" approach is required.

A huge obstacle to determining the risks of environmental agents in epidemiology is that we almost never know the trend in disease rates because we did not know the incidence at a baseline. Yet the couple of times that the USA has tracked human disease incidence over time, it again becomes rapidly visible that we are suffering a slow-motion chronic disease epidemic. Cancer incidence has been reliably measured for a few decades and has almost reached half of Americans, but I have uncovered research indicating that it used to be quite rare. As long-time readers of Rachel's know, big increases in recent decades are also seen in many birth defect categories, the second disease for which a partial baseline measure of incidence exists in the USA. Further indirect evidence that pollution has increased all chronic disease rates comes from health care costs in industrial vs. non- industrial areas of Ontario,[15] and from mortality during recessions and booms, reasonably controlled for socio-economic co- variates.[16]

The same observational tools revealing the subtlety of biology (signal transduction) are being employed to also reveal that toxins often operate at the low doses[17] we often encounter them at, instead of the unrealistically high doses we partly-test them at. The above- mentioned mass-produced exquisite hormonal mimic, the plastic molecule bPA, has 18 published studies showing an inverted (n-shaped) D/R curve -- not toxic at high doses but very toxic at very low doses. bPA begins to disrupt cultured cells beginning 30 seconds after a 1 picoMole (0.23 pg/ml) dose-roughly 217 million times lower than what the US-FDA and US- EPA say was the lowest dose that caused an adverse effect (50 mg/kg a day)![18] Many chemicals disrupt hormones, which are famous for functioning at very low doses and inactive at the higher doses at which are tested for risk at.[19]

Managing Toxic Risk: Human Experiment, or Precaution?

How is mankind managing such robust evidence of the toxicity risk of chemicals? Rachel's newsletter has long supported the Precautionary Principle (PP); and it has shown how the risk assessment (RA) practiced today by the regulatory agencies, which we have entrusted to keep us safe, is a total failure: RA fails to test the realistic (lower) concentrations of agents found in organisms, even as thousands of studies show toxicity at the beginning of our ability to detect these low dose toxicities. RA also ignores the complex mixtures that life is exposed to; and it tests toxins in adulthood -- a period of cellular senescence, compared to the complexity of development! But it is also worth noting that chemical RA still relies -- I believe deliberately -- on the visible-light microscope -- an observational method perfected almost 100 years ago; which relative to today's biochemistry methods contributes little to toxicology knowledge.

All three categories of causative proofs summarized above take years to carry out. Yet almost every chemical in commerce has been marketed without being tested for reasonable safety or need. For the few chemicals that are pre-market safety tested (drugs and pesticides), the party who will make millions or billions -- in annual revenue from the agent is the party that controls the testing which informs the determination! Even the European Union, which has just shifted this burden of proof (i.e. it is requiring a showing of relative safety before allowing chemicals to be sold, even for thousands of chemicals already on the market) will largely depend on the corporation to tell government if their money-maker is safe. In addition, the safety tests are done only at very high doses, where toxic effects may have little to do with the everyday exposure levels the biosphere experiences, even as low dose toxicity findings are becoming common. This is simply a global, ongoing toxicology experiment on the biosphere, including ourselves.

Taking again the example of bPA, a literature review showed that every one of the 11 published studies finding bPA was not toxic below "safe" level agency level were funded by corporations such as the producers of bPA and its products (by ignoring disease in positive controls and by using a lab rodent whose sensitivity to estrogens such as bPA had been conveniently bred to near zero)! In contrast, financially independent academic bPA researchers have found both positive and negative findings of low-dose bPA risk, but most all found toxicity: 40 studies found toxicity below the regulator's declared "safe" dose.[20]

bPA reveals the nub of the problem: the agencies we have tasked with protecting our health do not even test the doses we are exposed to and they rely on the profit-seeking producers of the toxins to tell them what the risk is! Many other agents already are known to show toxicity at doses organisms are exposed to.

Therefore the relevant social policy question for mankind regarding toxic agents is: how much initial evidence is needed to trigger action to reduce an uncertain risk? Well, the consequences if the risk is real are deadly and horrible; and as discussed, there is lots of initial evidence of toxicity at the doses we encounter; so obviously mankind should take more precaution than we are, and pay more heed to the toxicology data that is available.

In that regard, note one emotional argument used against implementing the PP: to act before having near-certain knowledge about a question of risk devalues the role of science. Activists respond: no, we need science to determine if precaution is needed or not. But we activists should engage even more science, because doing so throws this argument about "objectivity," and therefore trust, back to the destroyers of the biosphere. The subjective, industry money-driven "science" done for regulatory RA is not science, which is an open and critical-minded testing of hypotheses. Objective science strongly and increasingly suggests that the risks of toxic agents are horrific! Poison in the biosphere is one of the "Four horsemen of the apocalypse" (together with loss of habitat and of genetic diversity, and global warming). Scientists should always protect their key asset -- objectivity -- against misuse. But we activists and others always should use more of the fruits of that objectivity -- let us employ more science!

[1] M. Rechsteiner et al. 1976 "Turnover of nicotinamide adenine dinucleotide in cultures of human cells." J Cellular Physiology: 88: 2: 207-217.

[2] http://www.madsci.org/posts/archives/2000-05/9597873 88.Cb.r.html.

[3] Creighton, Thomas E., Proteins, (1984) W. H. Freeman & Co., p. 407.

[4] http://www.madsci.org/posts/archives/1998-10/9052 15349.Cb.r.html.

[5] http://stke.sciencemag.org/

[6] A.E. Taylor and others, editors, "The Physiology of Oxygen Radicals" Amer. Physiol. Soc. Bethesda MD 1986.

[7] U. Weiss (Ed.) 19 Dec. 2002 "Nature Insight: Inflamation," Nature:420:6917:845-889.

[8] wonderwhizkids.com/Chemistry/Organic+Chemistry/Functional+G roup/Organohalogen+compounds/Organohalogen+compounds+5.htm and wonderwhizkids.com/Chemistry/Organic+Chemistry/Functional+Group/Orga nohalogen+compounds/Organohalogen+compounds+6.html

[9] Vetter W, Gribble GW 2007 Nov. "Anthropogenic persistent organic pollutants -- lessons to learn from halogenated natural products." Environ Toxicol Chem.:26(11):2249-52.

[9] Kristin Schaffer et al. May 2004 "Chemical Trespass: pesticides in our bodies and corporate accountability." Pesticide Action Network N. America, San Fran. CA (http://panna.org); which extracted the pesticide data from the CDC's less-accessible overall NHANES-III data.

[11] Wozniak A.L. et al. 2005 "Xenoestrogens at picomolar to nanomolar concentrations trigger membrane estrogen receptor-a mediated Ca2 fluxes and prolactin release in GH3/B6 pituitary tumor cells." Environ Health Perspect 113:431-9.

[12] Landrigan, P. et al. 2007 "The Declaration of Brescia on Prevention of the Neurotoxicity of Metals." Amer J Ind Med:50:709-11.

[13] ATSDR/EPA Priority Superfund List, see http://www.atsdr.cdc.g ov/cercla/.

[14] See the Special Section "Metals: impacts on health & the environment." Science:300:925-47.

[15] Jerrett M. et al. 2003 May "Environmental influences on healthcare expenditures: an exploratory analysis from Ontario, Canada." J Epidemiol Community Health:57(5):334-8.

[16] Granados, J.A.T. 2005 "Point-Counterpoint -- Increasing mortality during the expansions of the US economy, 1900-1996." Int'l J Epidemiology:34(6):1194-1202.

[17] Welshons, W.V. et al. 2006 "Large Effects from Small Exposures. III. Endocrine Mechanisms Mediating Effects of Bisphenol A at Levels of Human Exposure." Endocrinology 147(6) (Supplement):S56-S69.

[18] Wozniak, A.I. et al. 2005 "Xenoestrognes at picomolar to nanomolar concentrations trigger membrane estrogen receptor-a mediated Ca2+ fluxes and prolactin release in GH3/B6 pituary tumor cells." Env Health Perspec:113:431-9.

[19] http://www.environmentalhealthnews.org/scienceback ground/2007/2007-0415nmdrc.html and I have about 30 published studies.

[20] vom Saal, F.S. and Welshons, W.V. 2006 "Large effects from small exposures. II. The importance of positive controls in low-dose research on bisphenol A," Environ Res 100:50-76.