Pesticide Exposure and Human Health (Part 1)\ ^ ' DONNA L HOUGHTON, Ph.D., SYNGENTA CROP PROTECTION CAN. INC.Turfgrass

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I n this article, the first of a two partseries, I will provide you with back-ground information that will help you

address public inquiries on this subject.This issue's article will focus on the regu-lation of pesticides in Canada, fundamen-tals of toxicology, acute toxicity ofpesticides in comparison with commonsubstances, misconceptions regarding thetoxicity of natural chemicals and the dif-ference between acute and chronic toxic-ity. Part two of this article will address theconcept of risk and allegations that pesti-cide exposure is responsible for varioushealth effects such as cancer and asthma.

Pesticides are products that are de-signed to kill unwanted living organisms;therefore, they need to be handled withrespect. They can be used safely becausethe dose required to cause serious healtheffects in humans is significantly higherthan the dose required to control the tar-get pest. The fundamental principle oftoxicology, which is the study of noxiouseffects of chemicals on living systems, isthat "the dose makes the poison." Thisprinciple was recognized many centuriesago but was not put into writing until theearly 1500s. "All substances are poisons;

there is none that is not a poison. The rightdose differentiates a poison and a remedy"[Paracelsus (1493-1541), the father oftoxicology].

Despite what the general public hasbeen led to believe, either by the media orvarious environmental groups, pesticidesare indeed regulated in Canada. In fact,Canadian regulations are the most strin-gent in the world and it is very importantto communicate this fact to the public. Inaddition, pesticides are the most highlyresearched and regulated group of chemi-cals sold in this country.

Canadian RegulationA pesticide cannot be sold in Canada

until it is "registered" by the federal gov-ernment. The term "registered" means thatthe product can be legally sold and usedas per regulations outlined in the PestControl Products Act (PCP Act). The Ca-nadian Pest Management RegulatoryAgency (PMRA) is responsible for re-viewing the scientific data on new prod-ucts submitted for registration by chemicalcompanies. The PMRA is very thoroughwhen reviewing data and it requires alengthy review period due to the large

quantity of scientific information that mustbe submitted by the pesticide manufactur-ers (100's of studies). New pesticide re-views conducted by the PMRA generallytake a minimum of 2 years. Pesticide sub-missions consist of the results of scien-tific studies that address the followingsubjects/questions regarding the newlyproposed product:

Chemistry (chemical information re-garding the active ingredient and the end-use product). The active ingredient is thechemical in the pesticide formulation thatprovides the desired mode of action, e.g.it provides the herbicidal, insecticidal orfungicidal activity. The terms "end-use

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product" or "formulation" refer to the ac-tive ingredient plus the liquid or solidmaterials added to the active ingredient tomake it suitable for handling, applicationor storage, e.g. water, solvents, clay, thick-eners and stabilizers. Formulations can beliquids, wettable powders, granulars, etc.

Toxicology. Results of studies conductedon laboratory animals to evaluate the po-tential for health effects such as cancer,birth defects, genetic mutations and effectson the reproductive and nervous systems

Metabolism. To determine how thechemical is metabolized (broken down) bymammals and plants

Residues. In the crop (agricultural sce-narios) and its by-products

Dietary, Occupational and By-stander Exposure. To determine thepotential for pesticide exposure to work-ers and bystanders during application orcontact with treated surfaces such as turfand/or dietary exposure through consump-tion of treated produce (agricultural uses)

Environmental Impact. To determineresidues in soil and water, environmentalfate and effects on non-target organisms

12 • JUNE 2002

Effectiveness. Results of performancetrials.

It can take up to 12 years from the timea chemical is discovered in the lab throughto the complete research and registrationprocess and cost in excess of $100 mil-lion (CDN) to bring one new active in-gredient and one of its correspondingend-use products to market.

Due to the stringent registration re-quirements in Canada, not all pesticidessubmitted to the PMRA are granted a reg-istration. In fact, it is currently very diffi-cult for a company to gain a registrationin this country. The PMRA's mandate isto protect occupational workers, the gen-eral public and the environment by ensur-ing that pesticides to be registered areeffective and can be used safely providedlabel directions are followed, and thus theagency plays a critical role in protectingCanadian citizens. The PMRA employsmore than 350 individuals to perform thistask and, understandably, they err on theside of caution to ensure that their man-date is achieved.

Toxicology PrinciplesBefore addressing whether or not ex-

po sure to pesticides causes an increasedrisk of certain health effects such as

asthma and cancer (Part 2), it is critical toexplain the fundamental principle of toxi-cology, the difference between acute andchronic toxicity, and misconceptions re-garding natural and man-made chemicals.

No doubt you have heard people talkabout how "toxic" one substance is com-pared to another. In this context, the term"toxic" generally refers to the acute tox-icity, or the adverse effects that occur fol-lowing a single or multiple exposures to asubstance within a 24-hour period. How-ever, some chemicals can also cause per-sistent health effects following exposureto lower doses continuously for long pe-riods of time. This type of toxicity is re-ferred to as chronic toxicity.

Toxicologists measure the acute toxic-ity of a chemical using a value known asthe LD50, which stands for Lethal Dose50%. Determining this value also makesit possible to roughly compare the rela-tive toxicity of various substances in ageneral sense (technically, the slope of thedose-response curve should also be stud-ied). The LD50 is derived from studiesconducted on laboratory animals (rats,mice and rabbits). Animals are exposedto the chemical either orally (via diet orstomach tube), dermally (applied to theskin), or via the inhalation route (breath-ing air containing the pesticide).

The dose, in milligrams per kilogramof body weight (mg/kg), which is lethalto 50% of the test animals within a statedperiod of time (usually 24hrs), is theLD50. When the chemical is administeredin the air, as it is in inhalation studies, tox-icity is measured using the LC50 or lethalconcentration in milligrams/litre of air(mg/L) required to kill 50% of the testanimals. The important point to remem-ber is that the lower the LD50 or LC50value, the more acutely toxic the substancebecause a smaller quantity will be lethalto 50% of the test animals.

Chemical OriginsThere is a common misconception

among the general public that natural sub-stances are "safer" than those that are man-made. The word "chemical" unfortunatelyconjures up negative images in the mindsof the public. In reality, all matter is com-posed of chemical building blocks calledatoms. Examples of atomic elements are

hydrogen, oxygen, carbon and nitrogen -there are over a 100 of them. Everythingin our world, natural and man-made, ischemical and is made of the same atoms- the food and water we consume, ourclothing, medicine, cosmetics, furniture,the plants in our garden, even our ownbodies ... and of course, the pesticides weuse.

What differentiates one substance fromanother is the number, combination andconfiguration of atoms that make up thesubstance. Once we accept that everythingaround us is chemical, we realize that whatpeople are really concerned about areman-made chemicals. Scientists have cre-ated new combinations and configurationsof these basic building blocks not foundin nature. Consequently, a whole host ofsynthetic products are now available e.g.plastics, pharmaceutical drugs and pesti-cides, to name a few. Many drugs and pes-ticides, however, are synthetic mimics ofcompounds found in nature e.g. syntheticpyrethroids.

While pharmaceutical drugs have aperceived health benefit in the minds ofthe public, pesticides are viewed as haz-ardous to human health because they areused to kill living things. In reality, thereare many substances to which people areroutinely exposed that are much moreacutely toxic than most pesticides. Themost toxic substance known to man is notman-made, it is a natural compound calledbotulinus toxin that causes botulism andis produced by a bacteria Clostridiumbotulinus. However, this toxin has beenapplied successfully in cosmetic surgerybecause extremely low doses are used.Remember, "The dose makes the poison."Nature has also produced many naturalpesticides such as pyrethrins and nicotinefrom chrysanthemums and tobacco, re-spectively.

Some chemicals have been used as bothdrugs and pesticides and may even haveadditional uses. For example, hydrochlo-ric acid has been regulated as a householdproduct when used in cleaning agents, adrug when used to treat people with lowgastric acidity and a pesticide adjuvantwhen used to enhance the germicidal ac-tivity of chlorine in swimming pools. Hy-drochloric acid is natural when producedby the stomach and synthetic when made

in the lab - even though its chemical struc-ture (arrangement of atoms) is the sameregardless of whether it occurs naturallyor is man-made. The toxicity of hydro-chloric acid is the same when it is used asa drug, a pesticide, a cleaning agent orwhen produced by the stomach. It is thedose in each of these cases that is differ-ent.

The fungicide thiabendazole has beenused successfully as a deworming agentin humans and animals as well as a fungi-cide for agricultural crops. Coumarin com-pounds such as warfarin are excellentrodenticides, but these compounds are alsovaluable anti-coagulant drugs. Many com-pounds that are screened for pesticide ac-tivity and are not accepted become drugsand vice versa. In summary, the toxico-logical properties of any chemical are in-dependent of its uses and whether it isnatural or man-made.

Potential for HarmAny chemical, if absorbed by the body

in excessive amounts, can be poisonous,even substances that are natural and sub-stances to which the public is exposed ona daily basis. It is well recognized thatsmoking is hazardous to human healthbecause it 'increases the risk of varioustypes of cancer including lung, mouth,throat, stomach, colon and prostate can-cers. What the public may not know, orfails to consider, is that nicotine isn't onlya carcinogen, it is a highly toxic substanceand it is natural - produced by tobacco.(In fact, nicotine was once used as a pes-ticide). Death does not occur after smok-ing a pack of cigarettes in a single daybecause the dose consumed is not highenough to approach an acutely toxic level;however, lower doses over the course ofmany years (chronic exposure) can beharmful.

Natural substances such as caffeine,salt, Vitamin D and gasoline are veryacutely toxic. Similarly, many pharmaceu-tical drugs are also quite toxic and can beharmful if taken in large doses e.g. Aspi-rin and Tylenol. Table 1 (pages 15-16) isdesigned to put the acute oral toxicity ofvarious chemicals into perspective. Thereader should keep in mind that the lowerthe LD50 value, the more toxic the sub-stance. Toxicologists do not calculate

LD50s in humans for obvious reasons, butfrom poisoning cases, the lethal doses ofcertain compounds have been docu-mented. Where available, these are in-cluded in the table. Table 1 demonstratesthat the idea that natural substances aresafe and man-made substances are toxicis a misconception. Over the centuries,many natural substances have been useddeliberately to cause death (e.g. the ex-ecution of Socrates using Hemlock brew).

The purpose of Table 1 is not to con-vey that pesticides are no more acutelytoxic than Tylenol and salt, but to demon-strate that people should keep their dose,which in the case of pesticides is their ex-posure, as low as possible to all of thesesubstances. Most people would never con-sider swallowing an entire bottle ofTylenol or a salt shaker full of salt. Theykeep their. dose to a minimum or, as in thecase of pharmaceutical drugs, they abideby the label recommendations regardingdose. The same is true of pesticides - thelabel regarding such items as applicationrate, personal protective clothing etc. mustbe followed in order to use the productssafely and reentry periods should be ob-served to protect bystanders.

The other basic type of toxicity ischronic toxicity, which can result fromlong-term daily .exposure to" a chemicalover the course of a lifetime (which inlaboratory animals is 18-24 months de-pending on species - this equates to a fullhuman lifetime). Several different chronictoxicity tests are performed which help topredict whether a pesticide will causelong-term health effects including can-cer.

Animals are exposed to a range of doselevels of the chemical, usually throughtheir diet, but occasionally through theskin or lungs, daily, for up to two years.The doses administered in a single studyrange from very low in some groups ofanimals, to extremely high in others. Thereis always a "control" group that is fed theuntreated diet and housed under identicalenvironmental conditions. During thestudy, animals are examined for physicaland behavioural effects. At the conclusionof the study, external and post-mortemexaminations are conductedand tissuesare examined microscopically. Theresultsfrom the treated and untreated groups of

SPORTS TURF MANAGER • .13

animals are compared. The results indi-cate whether or not a chemical has thepotential to be neurotoxic (toxic to thenervous system), carcinogenic (cancercausing), teratogenic (causes birth defects)or a reproductive toxin. Tests to determinemutagenicity (effects on DNA) are donein culture and also in live animals. Someof the mutagens we consume daily insmall quantities include chemicals in cof-fee.

Chronic toxicity testing is extremelycomplex. Health effects must occur in thestudy or it is deemed invalid and must berepeated at higher dose levels. All sub-stances, natural or man- made, will causehealth effects of some sort if given at ahigh enough dose.

The purpose of the chronic study is tostress the animals' system sufficiently foreffects to be seen. This allows the toxi-cologist to determine which organs are thetarget organs and to determine the high-est dose level tested that will not causehealth effects (a "safe" dose in the spe-cies tested). A minimum safety factor of

100 is then applied to this dose (e.g. thedose is reduced 100 fold, lOx to accountfor the study being conducted in animalsnot humans and an additional lOx to ac-count for differences between individualswithin a population) to obtain a dose levelthat is considered "safe" for human expo-sure. An additional lOx safety factor isinvoked if there is evidence of increasedsusceptibility of young animals to ensureour children are protected (total safety fac-tor = 1000 fold). A risk assessment is thenperformed by the PMRA to determine theexposure of the general public, bystand-ers and occupational workers to the newpesticide. Exposure values must be belowthe "safe dose" determined from the ani-mal studies following implementation ofthe required safety factors or registrationis not granted.

Turf SpecificPMRA reviewed the data on the prod-

ucts currently registered for use on turfand concluded that they could be appliedsafely without risking human health or the

environment (provided label directions arefollowed). Consequently, these productsare registered. As part of their ongoingreview program, PMRA is conducting re-evaluation of older pesticides that wereregistered prior to some of the newer studyprotocols and standards being required.Through re-registration, chemical compa-nies will be asked to fill data gaps on olderchemicals. These data will be reviewedand any products not meeting the stand-ard will have their registrations revoked.

Since the exposure incurred by occu-pational workers, bystanders and the gen-eral public has been thoroughly studiedfor each registered pesticide and found tobe well below any level of concern, thepublic's hysteria regarding their exposureto pesticides and risk to their health is cur-rently not warranted from a scientific pointof view. Pesticides can be used safely,provided label directions are followed;therefore, any pesticide ban approved bya municipality is really a political deci-sion based on emotion and not one basedon sound science. •

14 • JUNE 2002

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Table 1: Toxic Hazards of Common Materials

Note: Acute toxicity is measured following a single exposure. Where human data are available, the dose presented isthe lethal dose for adults unless otherwise noted. Lethal dose in mg/kg body weight has been calculated based on anaverage adult body weight of 65 kg. Acute oral toxicity from animal studies is assessed using the quantity required to killhalf of a group of test animals when given orally (Oral LD50); therefore, the higher the LD50, the lower the toxicity e.g. Alarger quantity of a less toxic substance is required to cause harm. Compounds in BOLD type are natural in origin.

LIST OF MATERIALS

PRIMO MAX

HERITAGE

ROUND-UP

ALCOHOL (ethanol)

KILLEX Lawn Weed Killer

ANTIFREEZE (Ethylene glycol)

GLYPHOSATE (active ingredient)

RUBBING ALCOHOL

(isopropyl alcohol)

DACONIL2787

SALT

DUAL® 960 (herbicide)

DISINFECTANT (Lysol®,7% O-phenylphenol)

HORIZON® Herbicide

AATREX NINE-0® (atrazine)

BANNER 130EC

ASA (Aspirin)

DICAMBA (active ingredient)

BLEACH

BATHROOM CLEANSER(Sodium phosphate 24%, eg. Comet®)

MECOPROP (active ingredient)

2,4-D herbicideformulations

LETHAL DOSE FOR HUMANS(from poisoning records; dose presentedin mg/kg body weight where possible)

10-14 oz or 300-400 mL pure etha-nol, or 600-800 mL 100 proof whis-key, if consumed in < 1 hr(3643-4860 mg/kg)1

8 oz or 227 mL (3751 mg/kg)2

100 mL = 100 g (1540 mg/kg)1

250 mL (3021 mg/kg)1

Lethal Dose for 1 yr old is 2 tbsp

10 g (2200 mg/kg)

200 g (3077 mg/kg)

15-30 mL (child) (500-1000 mg/kg)3

Approx. 50 g (769 mg/kg)

LD50 VALUES FROMANIMAL STUDIES (mg/kg

body wt unless otherwise stated)

>5050 (rat)

>5000 (rat)

>5000 (rat)

13ml_/kg(rat)

>5000 (rat)

8540 (rat)

5600 (rat)

4200 (rat)

3000-3750 (rat)

2780 (rat)

2480 (rat)

2276 (rat)

1600 (rat)

>1550

1350-1500 (rat)

1040-1707 (rat)

930-1166 (rat)

600-764 (rat)

REF.

a

b

b

c, d

b

c, d, h

e

c, d

b

f ,g,d

b

c, d

a

b

b

c, d, g

d, e

c

c

e

b, e

SPORTS TURF MANAGER • 15

LIST OF MATERIALS LETHAL DOSE FOR HUMANS LD50 VALUES FROM REF.(from poisoning records; dose presented ANIMAL STUDIES (mg/kg

in mg/kg body weight where possible) body wt unless otherwise stated)

CREAM OF TARTER (tartaric acid) 30 9 (462 mg/kg) c

TURPENTINE 15 9 (230 mg/kg) c

PROZAC 200-400 mg (14-17 yrs) (4-8 mg/kg)4 425-467 (rat) i, j, k

2,4-D (active ingredient) 375 (rat) b

CAFFEINE (coffee) 183-250 mg/kg 355 (male rat) c, f, d

100 cups of strong coffee 247 (female rat)

TYLENOL (acetaminophen) 10 9 (140 mg/kg) 338 (mice) c,d

DURSBAN TURF INSECTICIDE 776 (male rat), 300 (female rat) b

NICOTINE 40 mg (0.6 mg/kg = 1 drop = quantity 230 (mice) c,d

in 2 9 of tobacco or 2 cigarettes)

GASOLINE 10-250 mL (112-2807 mg/kg)2 c

MOTH BALLS (naphthalene) 2 9 (31 mg/kg) c

SODIUM FLUORIDE (fluorine) 5-10 mg/kg 35 (species not specified), 180 (rat) C, f, d

ARSENIC (Arsenic trioxide) 400 mg (6.2 mg/kg) 15.1 (rat) f, d

PARATHION 2 mg or 0.1 mg/kg (5-6 year olds) 2 to 13 mg/kg (rat) c, f, e, d

120 mg/kg (adult male)

1.8 mg/kg (no age specified)

VITAMIN D 10 mg/kg f

STRYCHNINE (Strychnine sulfate) 15-30 mg (0.2-0.5 mg/kg) Approx.5 mg/kg (rat) c, d

TUBOCURARINE CHLORIDE 6 mg/kg 0.63 mg/kg (mice, i.p.) c, d

BOTULIN (Clostridium botulinum) <0.000,014 mg/kg 9Food Poisoning

Referencesa) Internal Novartis/Syngenta Toxicology reportsb) Material Safety Data Sheets, various manufacturersc) Dreisbach, RH (1983) Handbook of Poisoning, 11th Edition, Lange Medical Publications. Note: amount fatal for adult divided by 65 kg typical

weight to get values in mg/kgd) Merck Index, Encyclopedia of Chemicals, Drugs and Biologicals (1983) 10th Edition, Windholz, M. Editor, Merck and Co. Inc., Rahway, N.J.e) The Pesticide Manual (2000), 12th Edition, British Crop Protection Councilf) Ottoboni, A (1984) The Dose Makes the Poison, Vincente Books, Berkeley, Californiag) Hayes, WJ and Laws, ER (1991) Handbook of Pesticide Toxicology, Academic Press, Vol. 1, 2 and 3h) Emsley J (1994) The Consumer GOOD Chemical Guide: A jargon-free guide to the chemicals of every day life. w.J. Freeman Co., New York,

pg.291i) Personal communication between Syngenta Crop Protection Canada Inc. and Eli Lily Canada Inc.D Product Monograph for Prozac, Eli Lily manufacturer, Feb. 21, 2000k) China Chemical and Pharmaceutical Co. Ltd., Taiwan

Footnotes1. Calculated using fatal dose converted to mass using density from Ref. d and body weight of 65 kg.2. Calculated using fatal dose converted to mass using density from Ref. b and body weight of 65 kg.3. Calculated assuming density of bleach containing 3-6% sodium hypochlorite in water is approx. 1, and 30 kg body weight.4. Assuming 50 kg body weight.

16 • JUNE 2002