Toksini i Mikotoksini

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Mixtures in the real world: The importance of plant self-defense toxicants,mycotoxins, and the human diet ☆

Joel L. Mattsson14155 Pepin Place, Carmel, IN 46032, USA

Received 17 February 2006; revised 28 November 2006; accepted 23 December 2006Available online 3 January 2007

Abstract

A perusal of research presented at the Annual Society of Toxicology Meetings, or in nearly any toxicology journal, will show that theoverwhelming emphasis of toxicology research is on synthetic chemistries. Because of substantial potency and exposure to natural chemicals, theoverwhelming focus on synthetic chemistries cannot lead to a realistic understanding of chemical risk to the general population. Natural chemicals,simply because of their abundance and potency, may be as likely to be a public health concern and to be involved in chemical interactions (natural:natural, natural:pharmaceutical; or natural:synthetic) as are environmental levels of synthetic chemicals. All plants have a mix of natural self-defense chemistries and mycotoxins that, when tested in a manner comparable to synthetic pesticides, cause the entire spectrum of toxic effects. Asa further complication, plants also escalate much of their self-defense chemistry when attacked by insects and fungi, and damaged crops often havehigher mycotoxins levels. Effective crop protection will typically reduce the plant's levels of self-defense toxicants and mycotoxins, but may addresidues of synthetic pesticides or add some other risk variable. In addition, cooking may also alter the food chemistry (e.g., acrylamide). Themixtures toxicologist needs to address the real world mixture of natural and synthetic chemicals. Public policy on crop-food safety cannot besensibly guided without these data and large voids in our understanding of risks from real-world mixtures cannot be in the public interest.© 2007 Elsevier Inc. All rights reserved.

Keywords: Plant self-defense natural toxicant; Mycotoxins; Food; Diet; Pesticides; Mixtures; Risk-assesment

Introduction

People are exposed to natural toxicants, pharmaceuticals,and synthetic chemicals. The purpose of this overview is toconvince toxicologists of the necessity to fully consider naturaltoxicants when evaluating risk of the public to environmentaltoxicants. The historical lack of systematic scientific andregulatory consideration of natural toxicants as an integral

part of the human experience must, by its absence, lead to anincomplete and possibly distorted understanding of overallchemical risk to human health. The concepts presented here aresimple extensions of arguments presented by Bruce Ames andLois Gold ( Ames, 1983; Ames and Gold, 1997; Ames, 2003 ).

As expressed in a biomonitoring paper by Paustenbach andGalbraith (2006 , p. 253): “ In fact, dietary exposure to thesenaturally occurring toxicants can greatly exceed any type of environmental exposures to these chemicals and the risks of dietary intake can also be appreciable. Rigorous analyses must consider that naturally occurring chemicals in the human diet may cause adverse health effects similar to those present due toindustrial processes. ”

Obviously, humans are exposed to complex and highlyvariable mixtures of natural and synthetic chemistries whichcreate opportunities for simple and complex interactions. Theterm ‘interaction ’ as used here is very generaland simply denotesthat, in one way or another, chemical A and chemical B (and perhaps C, D, and E) alter the biological effect of one another.

Although there is no thorough or systematic approach tostudy and regulation of natural toxicants, there are thousands of papers and many textbooks about the natural toxicants of plantsand plant foods. Most of the natural toxicant literature dealswith acute or sub-chronic exposures. Very few of these studiesare chronic or address mixtures or interactions. A small

Toxicology and Applied Pharmacology 223 (2007) 125 – 132www.elsevier.com/locate/ytaap

☆ Topic presented at the conference, Charting the Future: Building theScientific Foundation for Mixtures Risk Assessment. Atlanta, GA, Feb. 16 – 17,2005. The author was employed in 2005 by Dow AgroSciences LLC,Indianapolis, IN 46268. The opinions expressed in this paper are solely thoseof the author.

E-mail address: [email protected] .

0041-008X/$ - see front matter © 2007 Elsevier Inc. All rights reserved.doi:10.1016/j.taap.2006.12.024

mailto:[email protected]://dx.doi.org/10.1016/j.taap.2006.12.024http://dx.doi.org/10.1016/j.taap.2006.12.024mailto:[email protected]


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sampling of textbooks, by no means complete, would includeToxicants Occurring Naturally in Foods ( NAS, 1973 ), Toxi-cants of Plant Origin (Cheeke, 1989 ), Toxic Substances in Crop Plants (D'Mello et al., 1991 ), Handbook of Plant and Fungal Toxicants (D'Mello, 1997 ), and Foodborne Disease Handbook ,Volume 3 ( Hui et al., 2001 ). Even a casual reading of thesetextbooks will demonstrate that eating plants will inescapablyexpose us to a myriad of complex and potent chemistries,sometimes at surprisingly high levels.

The 624-page report on toxicants of foods by the NationalAcademy of Science ( NAS, 1973 ) was prompted by severalconcerns:

“ Perhaps the main one is the hope that it may contribute to amore informed, realistic, and sensible attitude on the part of the public toward the food supply ” (p. 2).

“ In any case, it is clear that the real challenge that we face isthe question of the long-term chronic toxicity, or lifetime

effects, of the known and yet unknown natural chemicalcomponents of our foods. Such effects that might result from ordinary patterns of consumption are of the greatest potential importance, since they would be expected to affect the largest number of people. Though the problem of carcinogenesis has been emphasized above, similar attentionshould be focused upon reproductive functions, mutagen-esis, cardiovascular – renal diseases, mental disorders, andother chronic ills of mankind of which the causes areunknown ” (p. 580).

Twenty-eight years later, similar concerns about naturaltoxicants of foods were expressed by Beier and Nigg (2001) :

“ We are exposed to a plethora of natural food chemicals asmixtures. … For those that have been tested, the testing procedures were limited in scope, design, and dose range ”(p. 133).

“ There are no guidelines or regulations regarding naturallyoccurring toxicants in food. … Do we know what we have placed in the marketplace? We do not. We have alwaysexperimented with foods on ourselves. A basis for chemicalchange(s) in our food supply should be established now. Wehave the tools and scientific talent to obtain the knowledgefor that base ” (p. 136).

For risk assessments of environmental mixtures of chemicalsto be scientifically rational, our exposure to natural chemicalsfound in foods cannot be ignored. Emphasis should be given tothose natural and synthetic chemicals that are most potent and towhich exposure is greatest. Good science is possible if bothnatural and synthetic chemicals are evaluated by the same set of toxicologic principles. There should be no double standard asexists at present ( Mattsson, 1996 ).

Interactions with ‘ natural ’ chemicals

Most of the recognized interactions between ‘natural ’ and‘synthetic ’ chemistries are between natural food chemicals and

pharmaceuticals. It is now recognized that furocoumarins ingrapefruit juice can sufficiently inhibit intestinal CYP3A4 tocause clinically-relevant, reduced first-pass metabolism of numerous pharmaceuticals. Bergamottin may be the most important furocoumarin for this effect in grapefruit juice, andconcentrations of bergamottin are about 12 to 25 uM ( He et al.,1998 ).

Murray (2006) reported on other potential dietary interac-tions with P-450 enzymes. Some common dietary constituentssuch as fats and carbohydrates can alter P-450 activity, andchemicals in teas and cruciferous vegetables may also inhibit human CYP enzymes. “ Thus, food constituents modulate CYPexpression and function by a range of mechanisms, with the potential for both deleterious and beneficial outcomes ” (Murray,2006 ).

Hu et al. (2005) have reviewed interactions between herbalmedicines and prescribed drugs, and many have caused seriousclinical problems. For example, hypericum (St. John's wort)

taken at the same time as oral contraceptives has beenassociated with breakthrough bleeding and unplanned pregnan-cies. In spite of the risk of interactions, the authors state “… theunderlying mechanisms for the altered drug effects and/or concentrations by concomitant herbal medicines are yet to bedetermined. ”

An editorial by Kaneko and Ishigatsubo (2005) warns that isoniazid, an effective and commonly used treatment for tuberculosis, can interact with fish, cheeses, or wines that have high histamine or tyramine contents. Isoniazid (INH) caninterfere with the metabolism of ingested histamine andtyramine, and “… the potential for frightening and dangerousinteractions between INH and certain foods is presently littleknown. ”

Alcohol is consumed world-wide, and the U.S. NationalInstitutes of Alcohol Abuse and Alcoholism ( NIAAA, 1995 )have stated “… many medications can interact with alcohol,leading to increased risk of illness, injury, or death. For example, it is estimated that alcohol – medication interactionsmay be a factor in at least 25 percent of all emergency roomadmissions. An unknown number of less serious interactionsmay go unrecognized or unrecorded. ” Natural contaminants of foods are also a concern. There are more than 350 types of mycotoxins that might be found in food or feeds ( Doerr, 2003 ),and concerns have been expressed about the likelihood of

interactions among mycotoxins ( D'Mello et al., 1997; Speijersand Speijers, 2004 ). Mycotoxin issues are discussed more fully below.

The following text will illustrate that many natural chemis-tries of foods have substantial potency and sometimes asurprisingly high content in foods, thereby increasing their likelihood as participants in interactions of public healthsignificance.

Exposure and potency

Toxicology is based on the principle that risk is a function of both exposure and potency. The body simply does not ‘care ’who or what made a chemical or why it was made. The only

126 J.L. Mattsson / Toxicology and Applied Pharmacology 223 (2007) 125 – 132


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relevant concerns are potency and dose. Since there is a great deal of public discussion as well as regulatory and researchemphasis on human exposure to pesticide residues in foods,these synthetic chemical residues will be used as a reference point for natural toxicants.

Synthetic pesticide residues in food

There is abundant information on pesticide residues in foods.The amount of allowable pesticide residue in foods is regulated.First, a wide variety of required toxicology studies areconducted, a relevant health effect is selected, and no-observed-adverse effects levels (NOAELs in mg/kg bodyweight) are determined. An allowable one-day intake limit iscalled an acute reference dose (ARfD, in mg/kg body weight),and is typically 1/100 of an appropriate acute NOAEL.Similarly, an allowable limit for lifetime exposure is called anallowable daily intake (ADI, in mg/kg body weight per day),

and is typically 1/100 of the chronic or lifetime NOAEL.Pesticide levels in food are regulated and monitored. Themaximum permissible residue levels, in ppm or mg/kg food, arecalled tolerances by the USEPA and maximum residue levels(MRL) in Europe. Tolerances are established for each pesticideand for each crop by integration of toxicology data (ARfD andADI), good agricultural practices, and expected humanconsumption.

Residues of synthetic pesticides in foods (including imports)in the United States in 2003 were below the limit of detection inabout 50% of sampled foods ( USDA, 2005 ). When detectable,residue levels were typically a small fraction of one ppm. For those fruits, vegetables and grains that had a pesticide detectionrate of 10% or higher, the mean amount of pesticide residue at the 90th percentile was 0.13 ppm, with a 90th percentile medianof 0.02 ppm. At the 90th percentile, the mean levels of pesticideresidues were on average only 2% of the tolerance, with amedian of 1% (derived from Appendix K, USDA, 2005 ).

About 24% of foods contained residue of more than one pesticide. Residues exceeded regulatory limits (tolerances) inabout 0.3% of samples ( USDA, 2005 ). While exceedingtolerance is a regulatory concern, the U.K. Pesticides ResidueCommittee ( PRC, 2004 , p. 24) states “ MRLs [tolerances] are set at levels that would not result in intakes high enough to causehealth risks. In most cases, residues at the MRL would result in

intakes considerably below both the ARfD and the ADI. So,even if a residue is above the MRL, this does not automaticallyresult in an intake above the ARfD or the ADI ” . To say thissimply: Wide safety margins are designed into the tolerances.Analytical results were similar in Great Britain ( PRC, 2004 ).About 70% of the samples tested had no detectable levels of pesticides, and about 1% of residues were above the regulatorylimit.

Natural toxicants of foods

Unlike synthetic pesticides that are vigorously tested andregulated to minimize human exposure to worrisome types of toxicity and to worrisome levels in our foods, the natural

toxicants of food plants are not similarly constrained. There arenumerous opportunities for toxicity and for interactions fromnatural chemicals of foods simply because of their great numbers and sometimes high levels.

The following references are but a tiny fraction of those inthe literature, but will illustrate the diversity and typicalconcentrations of natural toxicants in foods. In 1983, BruceAmes wrote a review of the substantial amounts of naturalcarcinogens in foods ( Ames, 1983 ). Ames stated that “ plants innature synthesize toxic chemicals in large amounts, apparentlyas a primary defense against the hordes of bacterial, fungal, andinsect and other animal predators ” (p. 1256). Ames' paper discusses many potential carcinogens that occur in the humandiet at trace to very high levels. For example, “ pyrrolizidinealkaloids are carcinogenic, mutagenic, and teratogenic and are present in thousands of plant species (often at > 1% by weight),some of which are ingested by humans, particularly in herbs andherbal teas and occasionally in honey ” (p. 1257).

Pyrrolizidine alkaloids (PA) are a recognized cause of humanintoxication, liver cirrhosis, veno-occlusive disease and liver cancer, particularly in Jamaica, India, and parts of Africa(Coulombe, 2001 ). In a referenced but non-peer reviewedcorrespondence, Daughton (2005) points out that regulatoryauthorities have identified PAs as a “ major human health threat,especially for fetuses and infants. ” In particular, Daughton(2005) identifies PAs as a missing but plausible candidate in theetiology of some specific cancer clusters because PAs can“ exhibit aperiodic cycles of high expression ” . Honey was citedas an example, since PA levels can vary “ two or more orders of magnitude within the same foraging location and by time of year. ”

Because of potentially high levels of PAs, the FoodStandards Australia New Zealand (FSANZ) released a con-sumer advisory on 9 February 2004 to limit consumption of honey from particular plants. Some batches of honey can attainlevels of PAs of 1 mg/kg, and levels of PAs found in variousgrain commodities in Australia have ranged from 6000 μ g/kg (ANZFA, 2001 ). The provisional tolerable dailyintake (PTDI) for PAs was established by ANZFA (2001) at 1 μ g/kg body weight per day, with a caveat that “ further characterisation of the potential human health risk fromexposure to PAs in food is not possible because there iscurrently inadequate dietary exposure information. ”

The U.S. National Research Council conducted an extensivereview of food carcinogens in 1996. While concluding that human risk of cancer from natural and synthetic carcinogens inour foods is low, the U. S. National Research Council ( NRC,1996 , Appendix A) provides data on natural chemicalconcentrations of some possible or probable rodent carcinogensfound in food: allyl isothiocyanate in horseradish (2000 ppm)and black mustard seed (10,000 ppm); benzaldehyde (found inover 40 foods) in white bread (5 – 10 ppm); capsaicin in hot red peppers (up to 10,000 ppm of dried fruit); estragol in basil andoregano (approx. 100 ppm), in tarragon (approx. 10,000 ppm),in anise and star anise (approx. 50,000 ppm); furfurol in cocoaand coffee (55 to 255 ppm), in wine (trace to 10 ppm), in manyfruits (trace to 1 ppm); safrole in cocoa, nutmeg, mace, black



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pepper (approx. 2000 ppm); benz[ a]anthracine in coconut oil(0.5 to 13.7 ng/g), in broiled fish (0.6 to 2.9 ng/g), in smokedfish (0.2 to 189 ng/g); benzo[ a ]pyrene in margarine (0.9 to36 ng/g), in broiled meat (0.17 to 50 ng/g), in smoked fish (1 to78 ng/g), ham (up to 14.6 ng/g), spinach (7.4 ng/g), tea (0.3 to15.8 ng/g). This listing demonstrates that many naturalcarcinogens or putative carcinogens are present in our foodsat levels that are far greater than synthetic pesticides.

Not all natural toxicants of plant foods are made by the plant or are external contaminants. There has recently been a great deal attention paid to levels of acrylamide in some fried andoven-baked foods ( Dybing and Sanner, 2003; CFSAN, 2005 ).Acrylamide is a natural product of high cooking temperatures incertain carbohydrate-rich foods, and acrylamide is mutagenic,carcinogenic, and neurotoxic. Concentrations from CFSAN,2005 data were highest in ground coffee (27 – 609 ppb), potatochips (505 – 1970 ppb), cereals (25 – 534 ppb), crackers (39 –1540 ppb), cookies (34 – 955 ppb), and other foods. Mean

dietary intake of acrylamide in Norwegian adults was about 0.5ug/kg/day. Intake at the 97.5 percentile was about 3× higher for adults and 4 – 5× higher in adolescents ( Dybing and Sanner,2003 ). When evaluated by linear extrapolation methods(Dybing and Sanner, 2003 ), carcinogenic risks from dietaryacrylamide were very high (90th percentile intake lifetimecancer risk for males was 13 cases per 10,000). Recently, theFAO/WHO Expert Committee on Food Additives ( FAO/WHO,2005 ) used Bench Mark Dose methods and calculated marginsof exposure for cancer (MOE=NOAEL/Exposure). For averageexposure, the MOE was 300, and 75 for those with highexposure. The committee expressed concern that these MOE'swere low for genotoxic carcinogens.

Perhaps the most studied of the plant self-defense toxicantsare the various glycoalkaloids (GA) of potatoes. GA are alsoabundant in green peppers, red peppers, and green tomatoes.Most self-defense chemistry of plants is located at the interfacewith the outside world. It is logical, therefore, that concentra-tions of potato GA are highest in the skins (300 to 600 ppm),and lowest in the flesh (12 to 50 ppm). Whole tubers containabout 10 to 180 ppm unless damaged. When stimulated by light (greened potatoes) or damaged physically or by infection, levelsof GA can soar (bitter tubers, 250 to 800 ppm) ( MAFF, 1996;Percival and Dixon, 1997 ).

Potato GAs cause acute gastrointestinal toxicity in humans at

about 2 mg/kg body weight, and cause serious neurologicaltoxicity and possibly death when exposure exceeds 3 mg/kg body weight ( Morris and Lee, 1984; Mensinga et al., 2005 ). Asnoted by Hopkins (1995) , this is a “worringly steep dose –response curve ” . If manufactured as a synthetic pesticide, theacute potency of GA would result in a WHO classification Ia,extremely hazardous (death


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The National Academy of Sciences ( NAS, 1973 ) statedconcerns about the health consequences of long-term dietaryhabits. A large, comprehensive study was conducted by Whiteet al. (2000a) based upon expectations that a long-termtraditional Japanese lifestyle, culture and diet would be protective of brain function, and acculturation to a ‘Western ’

lifestyle and diet would be a risk factor. The subjects wereJapanese that had immigrated to Hawaii, and the data ledrapidly to a focus on tofu and brain function and brain atrophy.The results were nicely summarized in an editorial by Grodsteinet al. (2000) : [it was found] “ contrary to their own and othersexpectations, that men who consumed greater amounts of tofuduring midlife appeared to score worse on cognitive tests, tohave lower brain weight and to demonstrate ventricular enlargement on MRI …” . Post hoc , the results were substantiallyreplicated in the men's wives who presumably had a similar diet. A criticism ( Guo et al., 2000 ) and further analyses wereconducted ( White et al., 2000b ), with no change in conclusions.

As White et al. (2000a) stated: “ In this study population, 20% to25% of the burden of cognitive impairment appears attributableto midlife tofu consumption – an effect size of enormous publichealth importance …” (pp. 252– 253). Although there are manycaveats about the meaning of these data, they do point to a needfor careful consideration of long-term dietary factors and humanhealth, and avoidance of assumptions about the health aspectsof foods in the absence of adequate data.

A change in consumption patterns of a traditional food canlead to health problems when safety margins are small. Avegetable (Sauropus androgynus) that is common in Malaysia became a ‘health food ’ for weight loss and other benefits inTaiwan ( Ger et al., 1997; Hsiue et al., 1998 ). For those seekinga health benefit, consumption increased from a typical one-meal per week (150 g) to about 130 g/day, and instead of cooking, the vegetable was often prepared as a juice althoughcooking was still common. Patients were mostly women, andmoderate to severe pulmonary disease (bronchiolitis obliterans)occurred in a dose-related fashion, and a small number of deaths occurred. The consumption period for 49 patients withobstructive lung disease ranged from 12 to 150 days (Table 3 of Hsiue et al., 1998 ), and the etiologic agent in the vegetable isunknown.

Plants are commonly invaded by fungi, and many fungi maketoxins of public health concern. For example, the prevalence of

neural tube defects (NTD) doubled among Mexican-Americanwomen along the Texas – Mexico border in 1990 – 1991 (Mis-smer et al., 2006 ). In 1989, there was an outbreak of equineleukoencephalomalacia that was particularly severe in Texas,and it was suggested that the equine outbreak and the human NTD outbreak were related to high fumonisin levels in corn. Theepidemiological evaluation of the NTD data supported the possible etiological role of corn fumonisins ( Missmer et al.,2006 ). A review by Marasas et al. (2004) indicated “ fumonisinsare able to inhibit embryonic sphingolipid metabolism and thisappears to interfere with folate utilization to produce embry-otoxicity and neural tube defects ” (p. 713). Marasas et al.concluded that diets low in folate but with elevated levels of fumonisins might be of particular concern.

Animals are more often afflicted with mycotoxin over-exposure, and Doerr (2003) nicely summarizes the dilemma:“ There are, perhaps, half a dozen or more mold genera withwhich we are usually most concerned (although there are many,many more that can adversely affect animals). Fusarium,Aspergillus, Alternaria, Penicillium, Stachybotrys, and Hel-minthosporium are representative of this group. For each genusthere are numerous toxigenic species. Many of those specieshave the capacity to produce more than one kind of mycotoxin,which, in part, accounts for the more than 350 recognizedtoxins. And, each, in turn, may infest those several feedcomponents mentioned above and leave behind one or moretoxic residues. What begins as our concept of a single mold and/ or single mycotoxin is seen by the animal as a multitude of toxicchallenges. ” D'Mello et al. (1997) state: “Routinely, animaltoxicity problems occur in which the quantity of the individualmycotoxins found in the suspected feed(s) does not explain theobserved syndromes. Currently, the combined effects of

mycotoxins on animal and human health have aroused concern because synergistic activities present a unique set of problems indefining both toxicity and food safety guidelines ” (p. 294).Concerns about interactions among mycotoxins have also beenexpressed by Speijers and Speijers (2004) . These concerns for possible interactions among mycotoxins, and between fumoni-sins and folate, demonstrate the potential interactive complexityof this class of chemistry. I have not yet identified papersdealing with possible interactions between mycotoxins andother potential toxicants of foods, or between mycotoxins andsynthetic chemicals, but these remain relevant questions.

Hammond et al. (2004) reported on fumonisin levels in U.S.corn from 107 locations. Over 3 years, total fumonisin levels in60% of the samples were above 2 ppm, which is the U.S. FDAguidance level for human food. Levels rangedfrom notdetectable(


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toxins of foods. It takes only a moment to recognize that thisis not true. Hardly anyone in the general public knows of thegreat variety and quantity of natural toxicants of foods. Thereis no systematic study of these natural toxicants ( Beier and Nigg, 2001 ), and certainly, there is no systematic education of the public about these toxicants. In contrast, synthetic pesticides are extensively studied, regulated, and monitored,and the public is constantly exposed to realistic and toalarmist information about synthetic pesticides in their food.Given that ‘organic ’ produce is now commonly available, andit is widely advertised that these products do not have‘ pesticides ’ , it could be argued that consumption of synthetic pesticides is far more voluntary than consumption of naturaltoxicants of foods.

Exposure to natural toxicants is under human control

Clearly, plants must have natural-pesticide defenses and

plants will commonly be contaminated by fungal toxins.Consequently, some people argue that ‘this is just the way it is’ . This perspective is, or course, incorrect. The levels of natural toxicants of plants are very much under human controlwhen this control is exercised. The profiles of natural toxicantsvary between different kinds of plants, and levels vary amongdifferent cultivars of a variety of plant (e.g., glycoalkaloids and potato variety; MAFF, 1996 , p.13). Humans make theselections, and these selections determine exposure. In addition,levels of many self-defense chemistries will increase with insect and fungal stress, and humans determine how this crop stress isto be managed ( Mattsson, 2000 ). Consequently, all of thesenatural-toxicant features are to a greater or lesser degree under human control.

Many think that using synthetic pesticides will simply add tothe burden already imposed by natural pesticides. This perspective is partly true and partly false. Plant self-defensesystems are both constituitive (at relatively fixed levels), or can be induced in response to crop damage ( Hammerschmidt andSchultz, 1996; Karban and Baldwin, 1997 ). Pesticide residueswill add to a plant's constituitive defenses, but if the pesticidesare effective in reducing crop damage, they will reduce the self-defense chemistries that are induced by damage. In addition, protected crops are less vulnerable to fungal invasion andmycotoxin contamination.

The biological complexity of plants leads to an important question: Is it safer to eat an insect and fungal damaged plant that has higher levels of stress-induced self-defense toxicantsand higher levels of fungal toxins, or to eat a plant that was protected with pesticides? Similarly, is it safer to eat a plant that was selected for natural, high levels of insect and fungalresistance to avoid synthetic pesticide residues, or to eat a plant with lower levels of natural defense that is augmented (whennecessary) by synthetic pesticides. At this time, there is littlespecific data to guide these decisions. These trade-offs are risk-versus-risk paradigms that are virtually unexplored but shouldcomfortably fit within the expertise of the mixtures toxicologist (see Hicks et al., 2000 , for an example with mycotoxins andfungicides).

There is limited protection from co-evolution

A comforting idea is that natural toxicants and humans haveco-existed since the beginning of time, so humans will havedeveloped resistance to natural toxicants. While partly true, it takes only a few moments to recognize that human tolerance tonatural toxicants of plants is limited. For example, humans areat an evolutionary disadvantage to most plants. The humanreproductive cycle is long compared to most plants, giving most plants an evolutionary advantage. Insects are in a far better evolutionary situation than humans, and yet plants are quiteeffective in keeping up with evolutionary resistance of insectsand fungi. If a plant's rate of evolving natural pesticides couldnot keep up with the evolving defenses of insects and fungi, this plant would cease to exist. It is an evolutionary war that does not offer a simplistic answer for human safety.

In addition, plants have ecological and geographic distribu-tions. If humans did not evolve in those locations, then there

was no opportunity for co-evolution. An example is thesolanaceous glycoalkaloids. Krasowski et al. (1997) speculatethat atypical genes for butyrylcholinesterase are especially highin geographic areas where foods that contain high levels of glycoalkaloids may have been consumed for thousands of years(South and Central America, Europe, some areas of the MiddleEast). These atypical genes occur at a very low rate in Africaand Asia where there was less evolutionary pressure fromglycoalkaloids.

Of all plants, humans can eat only a few. Survival specialistsrecommend you should eat only those plants or fruits that yourecognize as safe (U.S. Army Survival Manual FM 21-76). Todo otherwise is to put your life at risk. This simple observation points to the main evolutionary capability of animals; the abilityto learn which foods are safe or are safe under certain conditions(Pfister, 1999 ). Learning is far faster that co-evolution, but requires an ability to make an association between ingesting afood and a subsequent illness. Cognitive associations with foodthat promptly make you sick are readily remembered and cancause strong avoidance behaviors (even if the food itself was not the cause of the illness). It would be very difficult to learn anassociation to foods that cause toxicity only after chronicingestion or when illness occurs a long time after eating thefood.

Today, agriculturalists may select new plants for enhanced

pest resistance, or may use traditional methods to modify plantsfor increased pest resistance. There is no systematic evaluationof the safety of these traditionally-modified foods ( Fenwick et al., 1990 ), and there clearly is no evolutionary opportunity toadjust to quantitative or qualitative changes in pest resistancethat are being made today.

Natural and synthetic toxicology are the same

Some people argue that the human body somehowdifferentiates between natural and synthetic chemicals. Thereare, of course, many natural and synthetic molecules with whichhumans have minimal or no evolutionary experience. If this lack of evolutionary experience meant humans had no detoxification



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defense against ‘new to humans ’ molecules, it is hard to imaginehow the species has survived and has migrated world-wide.

Ames and Gold (1997) and Gold et al. (2002) haveaddressed this ‘natural versus synthetic ’ issue as a commonmisconception. A ‘generic ’ approach to detoxification is probably essential to survival, as a need for a specificdetoxification mechanism for each and every molecule innature is not imaginable. Toxicologists would be hard pressed toidentify molecules, with the exception perhaps of the verysmallest, that are ‘recognized ’ and detoxified as wholemolecules. The generic nature of detoxification is the key tomodern toxicology testing of synthetic chemistries. Systematictoxicology screening can provide a high degree of assurancethat, even if humans have never before been exposed to aspecific molecule, that this novel molecule can be reasonablydetoxified by those mechanisms that evolved against naturaltoxicants.

Mechanisms of toxicity appear to be the same for natural and

synthetic carcinogens. “Overall, the basic mechanism involvedin the entire process of carcinogenesis – from exposure of theorganism to expression of tumors – are qualitatively similar, if not identical, for synthetic and naturally occurring carcinogens ”( NRC, 1996 , p. 9.).

Summary and conclusions

Regulators and toxicologists are in an awkward ethical position in regards to hazard and risk assessment of naturaltoxicants. While we have the scientific tools, their applicationfor natural toxicants is conspicuous by its absence. As stated bySpeijers (1995) , “of most inherent plant toxins at best onlylimited data are available, which makes it impossible to performan accurate safety evaluation. This limited knowledge of inherent plant toxins permits the mystical claim of safety onthe basis of history of food use, and thus the development of specific food safety regulation has been postponed. ” Thisdeficiency in safety evaluation of natural toxicants is greatlycompounded by an absence of any realistic attempt tounderstand the role of natural toxicants as a significant component of everyone's daily exposure to chemicals, naturaland synthetic.

There appear to be no toxicologically meaningful differences between so-called natural and synthetic chemicals. In the body,

chemicals are chemicals, and risk of harm is driven by potencyand exposure. The natural:synthetic distinction may serve political and funding objectives, but availability of fundingappears to have grossly distorted the balance of toxicologicalresearch toward synthetic chemicals. Using synthetic pesticideresidues in foods as a point of reference, it is apparent that thereare far higher levels of natural toxicants in food than of synthetic pesticide residues. Ames (1983) estimated that “… dietaryintake of ‘natures pesticides ’ is likely to be several grams per day– probably at least 10,000 times higher than the dietaryintake of man-made pesticides ” (p. 1258). Beier and Nigg(2001) estimated that people might consume 60 ug per day of synthetic pesticides and herbicides, while natural pesticideconsumption is about 4.8 to 6 million ug/day. “ These numbers

result in a natural pesticide potential of 80,000 to 100,000 timesthat of synthetic chemicals in the diet ” (p. 132).

Although the exposure estimates of Ames (1983) and Beier and Nigg (2001) contrast natural and synthetic pesticides, theimportant point is not limited to pesticides. The point is that people are exposed to large amounts of natural toxicants in their daily lives, and the risk implications of these exposures arelargely ignored in contemporary toxicology. Essers et al. (1998)recommended that “ in light of the small safety margins for many inherent toxicants in plant food, there is a need for moreaccurate risk assessments of these substances in food. There isvery little data on these substances ” (p. 170). Essers et al. makeseveral recommendations on how to address food safety, and propose that priorities should driven by the severity of the healthrisk involved, the degree of human exposure, and the feasibilityof conducting a useful study.

While in general agreement with the proposals of Essers et al. (1998) , I would propose that we need to take one step further

back. As stated earlier in the paper, humans are exposed to amixture of natural and synthetic toxicants at the same time.Because of scarce resources, priorities should be determinedfrom our best estimates of risk to people from all chemicalsources. In this manner, there would be a realistic balance of studies on both natural and synthetic chemistries driven bysound scientific principles. Breaking down the artificialconcepts of natural and synthetic will foster opportunities todiscover interactions between natural:natural, natural:synthetic,and synthetic:synthetic, again based upon sound scientific principles. Only a realistic view of human exposure can lead torealistic risk assessments and risk management.

References

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