Radioactivity in the environment chapter 6 why chemical risk assessment can learn from radiation risk assessment

Radioactivity in the environment chapter 6 why chemical risk assessment can learn from radiation risk assessment Radioactivity in the environment chapter 6 why chemical risk assessment can learn from radiation risk assessment Radioactivity in the environment chapter 6 why chemical risk assessment can learn from radiation risk assessment Radioactivity in the environment chapter 6 why chemical risk assessment can learn from radiation risk assessment Radioactivity in the environment chapter 6 why chemical risk assessment can learn from radiation risk assessment Radioactivity in the environment chapter 6 why chemical risk assessment can learn from radiation risk assessment

Radioactivity in the Environment, Volume 19

ISSN 1569-4860, http://dx.doi.org/10.1016/B978-0-08-045015-5.00006-X

Why Chemical Risk Assessment can Learn from Radiation Risk Assessment

Carl F Cranor

Environmental Toxicology, University of California, Riverside, CA, USA

E-mail: carl.cranor@ucr.edu

6.1 INTRODUCTION

The biological models for radiation and many chemicals have been seen as having substantial differences Radiation has no lowest exposure at which adverse health effects result and the dose–response curve has been assumed to

be linear from levels at which it can be measured to the no-exposure level— lower doses are less likely to cause adverse health effects, but they are never nonexistent In contrast, at least some chemical exposures have been assumed to have threshold effects for individuals, exposure levels below which for a chemi-cal taken in isolation no adverse health effects occur Thus, although there can

be exposures above the threshold at which humans are adversely affected, once exposure is less than the threshold level, there are no adverse effects However, thresholds might be different for different individuals and identifying thresholds for populations is more difficult (more on this below)

Chapter Outline

6.1 Introduction 87

6.2 Some Principles and

Presumptions of Radiation

6.3 Contamination 90

6.4 The Developmental

Basis of Disease 92

6.5 Contamination of

Developing Children 92

6.6 Adverse Health Effects 93 6.7 Particular Substances

have No Obvious

6.8 A Unified Approach

to Dose-response

6.9 Conclusion 100

The picture just described no longer seems applicable or at best quite mis-leading The emerging science of the developmental origins of disease reveals that very low, even tiny, doses that would not contribute to harm in adults can contribute to harm in developing children At odds with the chemical threshold model, researchers have identified some substances that appear to have no low-est safe dose (at least, to date), much like radiation More importantly, since we now live in a world in which people are surrounded and permeated by chemi-cal substances and we have different individual thresholds for adverse effects, even if particular chemicals act by means of threshold mechanisms, these con-ditions together suggest that responses to chemical contamination should begin

to incorporate policy responses similar to those of radiation in order to properly protect the general public The upshot is that protection from chemical expo-sures should begin to incorporate presumptions of no threshold in order to pro-tect the public This presumption could be overridden only if there were good evidence contrary to the background conditions of the presumption

6.2 SOME PRINCIPLES AND PRESUMPTIONS OF RADIATION PROTECTION

Radiation can produce two different kinds of effects on humans: tissue reactions

and stochastic effects “Tissue reactions…are characterized by a threshold dose, above which the effects always occur … Tissue reactions are caused by the extensive damage or killing of living cells in organs and are generally limited

to accidents or controlled medical circumstances” (Wikman-Svahn, 2012) In

contrast, stochastic effects “do not necessarily occur in an exposed individual,

but with a certain probability Stochastic effects are caused by modification of cells (e.g damage to the DNA), which may lead to the development of cancer and hereditary diseases” (Wikman-Svahn, 2012)

Somewhat oversimplifying, the different biological reactions lead to two different models: tissue damage effects are based on the idea that the threshold dose represents a cutoff between damage and no damage Below the threshold

no damage is presumed to occur, but above the threshold the tissue effects occur

in an exposed individual In contrast, “the risk of stochastic effects is best repre-sented by a linear dose–response relationship—the so-called linear no-threshold (LNT) model” (Wikman-Svahn, 2012)

In what follows in order to contrast adverse effects from chemicals with adverse effects from radiation I focus on stochastic effects and the linear no-threshold (LNT) model The stochastic model seems appropriate for both cancer risks and for hereditary risks, or risks to the germ cells of person that are passed from one generation to another Per Wikman-Svahn, in a recent doctoral dissertation from the Royal Institute of Technology, summarizes the main conclusions concerning these effects “The mainstream scientific view

on these matters … is that a threshold for stochastic effects is not likely and

that a linear dose–response relationship for small doses is more credible than other alternatives This linear relationship does not necessarily apply to each individual or each cancer type, but is seen as representing the average response

in a population and over all cancer types.” The LNT model does generate some disagreement; some scientists believe that it underrepresents risks from radia-tion, because at low doses radiation causes more damage than the linear model suggests, while others believe that it overestimates risks because of its linearity (Wikman-Svahn, 2012)

Despite some degree of disagreement within the literature, for what follows below I assume that for cancers and adverse hereditary effects from radiation exposure the LNT model best describes the biology For exposures to chemicals early in the history of chemical carcinogenesis scientists appeared to believe that chemicals similarly contributed to harm by means of a simple linear model Subsequent research for carcinogenesis has shown that there are various mecha-nisms for cancer, not all occurring by means of LNT effects and not caused by

a single hit from a chemical

More recently, there has been more emphasis on threshold models for non-cancer harms caused by chemicals Certainly, in regulatory or tort law contexts

in the U S industries subject to regulation or to personal injury suits often emphasize the threshold models to explain adverse effects from chemical sub-stances The reason seems clear: if there are exposures to the chemical that are below the presumed threshold, then there is no case for reducing exposures

to the substance and there is no legal case to be made in the tort or personal injury law that an individual exposed to chemicals below the threshold has been harmed by the exposure A clear biological border between harm and safety makes certain legal arguments much easier, and if a threshold has not been exceeded, this tends to remove the legal rationale for regulatory action and to exonerate a company from tort suits

Recent scientific research and some subtleties about mechanisms for harm from chemical exposures throw this overly simple assumption into question In what follows I summarize some recent scientific findings that suggest myriad exposure circumstances support an argument for a policy and legal approach to chemical exposures that more closely resembles the legal and policy response

to radiation than the threshold model In short, despite biological evidence for threshold effects from exposures to some individual chemicals, a general approach that emphasizes the threshold model seems to be misplaced Wise policy to protect the public from harm from chemical exposures should shift this presumption It seems much better to presume that chemical exposures contribute to harm by means of something like a no-threshold model than

a threshold model Only if there is good evidence for a threshold approach, given all the exposure conditions and all that is known about the biology of the chemical in human bodies as we find them, should a threshold approach

be followed

6.3 CONTAMINATION

The U.S Centers for Disease Control (CDC) has a biomonitoring program that has testing protocols for measuring the amounts of industrial chemicals

in a person’s blood or urine in order to determine concentrations in his or her body Such measurements identify the concentrations of substances in one’s body from, “all routes of exposure—inhalation, absorption through the skin and ingestion, including hand-to-mouth transfer by children.” More importantly, biomonitoring reveals the integrated effect of different exposures to the same substance (Sexton, Needham, & Perkle, 2004)

Moreover, the CDC chose the particular substances for investigation because they either constitute substantial exposures or are known or suspected toxic

haz-ards or both They are called chemical hazhaz-ards because they have intrinsic toxic

properties or a “built-in ability to cause an adverse effect” (Faustman & Omenn,

2001; Heinzow, 2009)

The CDC’s research is revealing the extent to which U.S citizens are con-taminated by substances of concern In 2005, the CDC had reliable protocols to identify 148 industrial chemicals in citizen’s blood and urine (U.S Department

of Health and Human Services, Centers for Disease Control and Prevention, Third National Report on Human Exposure to Environmental Chemicals, 2005)

In 2009, it had protocols for 212 substances (U.S Department of Health and Human Services, Centers for Disease Control and Prevention, 2009) Currently,

it lists more than 300 environmental chemicals or their metabolites in the U.S citizens (U.S Department of Health and Human Services, Centers for Disease Control and Prevention, Environmental Chemicals, 2013)

The significance? Each person is contaminated to a greater or lesser degree,

as various studies have shown (more below) Humans are not just exposed to industrial chemicals external to their bodies, but the substances enter our bodies via inhalation, ingestion, or skin absorption Beyond this, they invade our inter-nal tissues and biological processes According to Larry Needham, Director of the program, all but the very largest macromolecules will invade our bodily tissues and be processed by various metabolic routes (Needham, 2007)

As Environmental Defense puts the point based on a small study of Canadians, “No matter where people live, how old they are or what they do for

a living, they are contaminated with measurable levels of chemicals that can cause cancer and respiratory problems, disrupt hormones, and affect reproduc-tion and neurological development” (Environmental Defense, 2005)

Moreover, since all of the substances identified to date are known or suspected toxicants, these findings are worrisome Of special concern is that industrial chemicals can penetrate deep into a person’s body For example, when

a woman is pregnant, most industrial chemicals, pesticides, and pharmaceuti-cals can cross the placenta and enter the womb, depending upon such prop-erties as size, electric charge, fat solubility, and so on As one of the leading experts puts the point, “It is clearly evident that there really is no placental

barrier per se: The vast majority of chemicals given the pregnant animal (or woman) reach the fetus in significant concentrations soon after administration.” (Schardein, 2000) Such substances can even contaminate the very tissues that

go into creating a child before parents ever decide to have a child This includes women’s eggs and men’s sperm, genetic sources of children In addition, many other tissues in their bodies have intimate contact with industrial chemicals Once a child is born and begins nursing most substances can similarly enter the breast milk, be conveyed to the child and transfer some of a mother’s body burden of industrial chemicals to the child (Heinzow, 2009) The consequence

is that even the youngest, most innocent, and seemingly the most pristine of humans experiences intimate contamination of their tissues and bodily organs from conception onwards

Unlike nuclear radiation, for which many or most sources tend to be associ-ated with workplaces, chemical contaminants are all around us and very close

to home When we use cosmetics or sunblock, we absorb some phthalates through the skin Some lipsticks can add to the lead in one’s body that is present from past exposures to leaded gasoline, lead paint or deposited in the environ-ment Tap water or vegetables contain small amounts of a component of rocket fuel, fireworks, or munitions, perchlorate Furniture, drapes, electronic equip-ment, including television sets and computers, contain some brominated fire retardants, polybrominated diphenyl ethers (PBDEs) They are not chemically bound to the fabrics or plastics, but are merely mixed in, so over time they can disperse into our homes, house dust and ultimately into our bodies In the U.S., concentrations of PBDEs in citizens’ bodies are rapidly increasing even though some steps have been taken to reduce the production and use of some of these chemical products Recently created chemicals in domestic and international markets are not the only concern; legacy chemicals such as PCBs and DDT have been in the environment and in our bodies for decades PCBs and the more recent PBDEs travel around the world, enter the ocean, and contaminate ecosys-tems and animals (Cone, 2005) Indeed, PBDEs have been found in Tasmanian devils, hundreds of miles from any industrialized society (Denholm, 2008) Phthalates appear to contribute to premature breast development, sex organ problems in males and some reproductive and developmental risks (Rawlins,

2009; Swan et al., 2005) Lead is a well-known neurotoxicant, adversely affect-ing learnaffect-ing, IQ, and behavioral controls It also contributes to cardiovascular dis-ease Adverse effects can occur at surprisingly low concentrations and for some

no known safe level has been identified (Navas-Acien, Guallar, Silbergeld, & Rothenberg, 2007; Wigle & Lanphear, 2005) Perchlorate in water can be a spe-cial problem for pregnant women, children developing in utero or even newborns Perchlorate can interfere with thyroid hormones needed for brain development Pregnant women who have too little circulating thyroid hormone may adversely affect their children’s brain development; chemical exposures can contribute to this problem When young children have too little thyroid hormone, this can interfere with brain development (more below) (Woodruff et al., 2008)

6.4 THE DEVELOPMENTAL BASIS OF DISEASE

Major scientific developments associated with what is now being called the

“developmental origins of health and disease” (which I will largely refer as the developmental origins of disease) are leading to a reassessment of the sensitiv-ity of humans to toxic substances Several considerations support this research: the placenta that had been seen as protecting a developing fetus is no longer considered a barrier to many toxic substances; scientists now understand that humans are exposed to many more substances and exposed earlier in life than previously; during in utero and postnatal development, humans (and mammals more generally) are quite sensitive to toxic influences; and, finally, these effects are exacerbated by a number of other factors I consider each of these in turn This research does not necessarily show that a threshold model of toxicity is not correct at least for quite limited circumstances, but it strongly suggests that any thresholds can be quite low and much lower for developing children than for adults However, once this information is combined with data about exposures

to myriad substances as well as the additive and sometimes-synergistic effects between substances, this supports a presumption for adopting a nonthreshold model for chemical toxicants

6.5 CONTAMINATION OF DEVELOPING CHILDREN

As introduced above, James Schardein points out, “there really is no placental barrier per se … ” (Schardein, 2000) Toxicologists Rogers and Kavlock (2001)

concur: “virtually any substance present in the maternal plasma [blood] will be transported to some extent by the placenta.” These findings reject an older view

of the womb as a safe, protected capsule within which a child develops, follow-ing its own genetic program In contrast, it is probably better to understand the

womb within a woman’s body as an internal environment that provides food,

fluids, and sound (Soto, 2007) However, if this environment contains toxicants,

as we now know that all human bodies do, a developing child is exposed to those substances as well This internal “environment” can expose a child to toxicants by the same routes that provide nourishment and fluids

Because the placenta constitutes no, or is at best a limited, barrier to chemi-cals, any contamination of a pregnant woman is likely shared with the children developing in utero For instance, despite the sound advice for mothers to nurse their newborns, nursing does not protect infants from toxicants A nursing child begins to ingest toxicants from its mother’s body from its first drink In effect, this transfers some of a mother’s body burden of industrial chemicals to the child (Heinzow, 2009)

Consequently, for the above reasons children are not protected from chemi-cal substances until they are born and enter the world as independent living beings; they are contaminated in utero and are born already tainted by indus-trial chemicals, many of them known toxicants A news article reported that newborns were tainted with up to 200 industrial chemicals (Fimrite, 2009)

A scientific study in Minneapolis found a significant proportion of children from poor sections of the city have been found contaminated with more than 75 substances or their metabolites: phthalates, metals [lead, mercury], organophos-phate pesticides, organochlorine pesticides, polychlorinated biphenyls (PCBs), volatile organic compounds, cotinine (an ingredient in cigarette smoke), envi-ronmental tobacco smoke (ETS) (Sexton, Ryan, Adgate, Barr, & Needham,

2011) All the contaminants include known or suspected carcinogens, endo-crine disrupters, neurotoxicants, and developmental and respiratory toxicants

At some concentration level all of these will pose risks of disease; some acting alone may cause harm by threshold mechanisms, while others may contribute

to harm by linear mechanisms One small study found 232 industrial chemicals

in the umbilical cords of newborns (Environmental Working Group, 2009) As a consequence, scientists now understand that humans are exposed to many more substances and exposed earlier in life than previously

6.6 ADVERSE HEALTH EFFECTS

Developing children are especially vulnerable to adverse health effects and typi-cally much more susceptible to them than adults because they are in one of the most sensitive life stages Whatever organ system one considers—the brain, the immune system, reproductive system, or the lungs—each is typically much more vulnerable to toxic harm than the same system in adults While not all exposures during development will contribute to adverse effects, the fact that developing children are especially sensitive to toxicants is quite worrisome Moreover, developing children are typically subject to greater exposures than adults on a body weight basis According to the consensus statement of first conference on the developmental origins of disease, “the mother’s chemical body burden will be shared with her fetus or neonate, and the child may, in some instances, be exposed to larger doses relative to the body weight” ( Grandjean

et al., 2008) Methylmercury concentrations in the fetal brain can be as much

as five times greater than concentrations in the mother’s blood (Grandjean

et al., 2008; Honda, Hylander, & Sakamoto, 2006) Breast-fed infants may have greater concentrations of lipophilic (fat soluble) toxicants, since breast milk contains considerable fat For instance, a nursing child’s daily dose of PCBs in the breast milk “may be 100-fold higher” than the concentration of the PCBs in the mother’s blood “resulting in much greater toxic concentrations in the child than in the mother” (Grandjean et al., 2008) Not all lipophilic toxicants will show similar increases in breast milk, but this seems to be the case for PCBs

In addition, during development children have lesser defenses than adults

A child’s immune system is not developed in utero or at birth A mother’s immune system offers some protection for the child in utero, but her immune system offers less protection for each of them of them considered separately than it would for the mother alone (Talbot, 2009) The blood–brain barrier, which evolved to protect the brain from some toxicants, does not develop until

about six months after birth Once developed it imparts protection against some chemicals entering the brain Similarly many enzymes that can detoxify toxic substances are often poorly developed in young children, resulting in greater toxic insults to children than adults from industrial contamination

(Interest-ingly, some enzymes that increase the toxicity of comparatively less toxic

substances may not have matured, so sometimes children can have greater protection than adults.)

The points above represent a few of the general or typical biological tenden-cies of developing children that can increase their vulnerability to toxic insults However, when genetic variability and diversity are considered, the range of adverse effects increases

For instance, vulnerability to organophosphate pesticides can “vary by age and genotype.” Children as well as adults with a variant of a particular gene have lower levels of an enzyme that assists in metabolizing organophosphate pesticides Having less of this particular enzyme puts them “at higher risk of health effects from organophosphate exposure.” (Eskenazi et al., 2008) Poten-tial effects include neurotoxic effects as well as some cardiovascular endpoints (Ecobichon, 2001)

For another example, polycyclic aromatic hydrocarbons (PAHs), formed during incomplete combustion of organic compounds from the combustion of coal, gas and oil, and from side stream and secondhand tobacco smoke can cross the placenta and bind to (or create adducts on) DNA (Perera, Jedrychowski, Rauh, & Whyatt, 1999) This typically alters the DNA’s function and causes mutations or incorrect repair leading to cancers or other diseases Subpopu-lations of fetuses with more PAH-DNA adducts show increased sensitivity to genetic damage compared with the mother and compared to others (Miller

et al., 2002; Perera et al., 1999) This can lead to smaller head circumference, associated with other adverse effects, as well as genetic damage in the newborn (Perera et al., 1999)

As a consequence, while an average or typical child might not be susceptible

to a particular contaminant at a particular concentration, human genetic vari-ability can increase or decrease the extent of sensitivity This fact of biology increases the range of susceptibility of developing children to adverse effects compared with adults

The greater vulnerability of developing children to disease has a further con-sequence less typical of adults Because young children have more years of future life ahead of them than adults, if children are contaminated with toxicants before they are born or in early childhood, and disease processes are quickly initiated, there is more time for diseases or dysfunctions to fully develop so they can be clinically detected during a lifetime A disease process might require one, two or three critical steps to occur before the disease is fully initiated How-ever, if one or two steps occur in utero, as DES likely did, or in early childhood,

as occurs with lead, then fewer steps would need to occur later in life for full-fledged disease or dysfunction to appear (Heindel, 2008) Miller et al (2002)

point out, “Cancer is a multistage process and the occurrence of the first stages

in childhood increases the chance that the entire process will be completed, and

a cancer produced, within an individual’s lifetime.”

The general vulnerability of children plus greater exposures and (gener-ally) lesser biological defenses than adults have resulted in risks of diseases for developing children All of these processes are exacerbated by genetic variation that can increase vulnerability to toxicants Moreover, toxic effects in develop-ing children usually occur at much lower concentrations than those that cause adverse effects in adults

Adult humans who ingested fish contaminated with methylmercury from Minimata Bay in Japan suffered adverse effects, but children who were con-taminated in utero experienced quite catastrophic effects (Honda et al., 2006) Children contracted cerebral palsy at 10 times the rate of unexposed children and a number died (Weiss, 1994) In part, this occurred because they had much greater exposures to methylmercury in the brain, which has a selective affinity for it, and, of course, they were in general much more susceptible to adverse effects than adults (Honda et al., 2006)

In utero exposure to the synthetic estrogen diethylstilbestrol (DES) caused dramatic rates of early life vaginal cancer in young women (about 20 years of age) and also increased breast cancer in DES daughters as they reached middle age (Kortenkamp, 2008) DES mothers do not appear to have suffered can-cer of the reproductive tract, but have subsequently experienced an elevated rate of breast cancer because of DES they took decades earlier (Titus-Ernstoff

et al., 2001) Similarly, while Thalidomide caused some peripheral neuropathy

in some women who took it, this sedative generally seemed to have benefited them However, developing children exposed in utero to the Thalidomide their mothers’ ingested suffered terrible physical abnormalities and birth defects along with neurological problems (Landrigan, Kimmel, Correa, & Eskenazi,

2004) Some anticonvulsive drugs can reduce convulsions in women prone to them (for example, because of epilepsy), but can cause birth defects in children exposed to them in utero (Landrigan et al., 2004)

Children have higher rates of leukemia and thyroid cancer from radia-tion exposure than adults at similar exposures Teenage women exposed to radiation tend to have higher rates of breast cancer than older women simi-larly exposed (Miller et al., 2002) In addition, women younger than 14 who were exposed to greater concentrations of DDT when it was in widespread use in the U.S contracted breast cancer at a fivefold higher rate than older women with similar exposures (Cohn, Wolff, Cirillo, & Sholtz, 2007) For developing children whose blood–brain barriers have not developed, cadmium and monosodium glutamate can “enter the developing brain freely” (Rodier,

1995) Some hormones can have adverse effects at exceedingly low levels For instance, Tamoxifen, which is now used to treat breast cancer, promotes can-cer at two or more orders of magnitude below therapeutic levels (Vandenberg

et al., 2012)

To this point I have mentioned adverse effects in humans who were exposed

to one substance at a time However, as presented above, a more realistic under-standing of exposures is that we are all routinely contaminated by multiple industrial chemicals, many of them toxic

Some substances add to the toxic effects of other compounds This is seen with estrogen mimicking compounds, dioxin-like compounds and androgen antagonists That is, some substances add their toxic effects together because toxicants and naturally occurring biochemicals in the body attach to the same cellular receptor (Simon, Britt, & James, 2007) For estrogens, it appears that a woman exposed to more estrogen from endogenous or exogenous sources over

a lifetime is at greater risk for breast cancer (Kortenkamp, 2008) Thus, when

a person is contaminated by toxicants that attach to the same receptor, this can increase risks of any diseases they cause

In addition to this point, there are more general additive effects that pose concerns Woodruff et al (2008) have discussed several compounds that can function via different biological pathways but that cause the same adverse effects For example, pregnant women need sufficient levels of thyroid hor-mones to facilitate proper neurological, including brain, development of their children If circulating thyroid hormones are too low in a pregnant woman, a developing child can experience poor brain development Women could have insufficient thyroid hormones because of their circumstances, e.g too little iodine in their diets However, even if this were not the case, Woodruff et al have shown that one class of substances, e.g dioxins, dibenzofurans and dioxin-like PCBs, adversely affect one group of liver enzymes reducing thyroid hormones, while another class of compounds, e.g nondioxin-like PCBs, affect different liver enzymes that also reduce circulating thyroid hormones It also appears that the brominated fire retardants (PBDEs) along with perchlorate, a discarded rocket fuel and fireworks component, can also contribute to similar adverse effects, but by two additional and different pathways (Woodruff et al., 2008) Thus, although the four classes of substances act by four different biological pathways, the substances produce “a dose-additive effect on [thyroid hormones]

at environmentally relevant doses … demonstrating exposures to chemicals act-ing on different [biological] pathways can have cumulative effects…” Conse-quently, “It is appropriate to presume cumulative effects unless there is evidence

to the contrary, and it is important for risk assessments to consider real-life exposure mixtures” (Woodruff et al., 2008)

When the above research is combined with the data indicating that humans are contaminated by a number of substances, this shows that people can be much more vulnerable to toxic insults than had previously been considered The conceptual point is that if a population had no exposures to other substances that could contribute to the same adverse endpoint and no special biological suscep-tibility, then exposures from a single substance might cause no adverse effects

in the population However, when co-exposures are considered, even without any biological susceptibility to the exposures, the co-exposures plus a new