6-toxicologyabcs

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JOURNAL OF PESTICIDE REFORM/WINTER 2001 VOL. 21, NO. 4

S K I L L S

The world of toxicology can bemind-boggling. Many of us have beenin situations in which weve gatheredtogether information about chemicalsand their health effects, only to findthat we dont know how to decipherit. Whether the information comesfrom journal articles, governmentdocuments, or newspapers, radio andTV, we cant figure out what it allmeans.

This article provides a brief intro-duction to basic toxicology terms. Wehope this information will help youmake sense of what you read and what

you hear. It focuses on pesticidesrather than all chemical and physicalagents, and on humans as opposed toother living organisms.

What is Toxicology?

Toxicology is often defined as thestudy of the nature and mechanism oftoxic effects of substances on livingorganisms and other biologic systems.1

In simpler words, Toxicology is thestudy of the adverse effects of chemi-cal and physical agents on living or-ganisms.2

Frequency and Duration ofExposure

Frequency of exposure refers to thenumber of times a person is exposedand the time between exposures. Du-ration of exposure can be acute,subchronic, or chronic. Acute expo-sure is once or twice in a short periodof time, such as a week or less.Chronic exposure is long-term or life-time exposure and spans at least 10percent of a lifetime. For humans, thisis considered seven or more years.Subchronic exposure is somewhere inbetween acute and chronic, and it

ABCSOF TOXICOLOGY:

BASIC DEFINITIONSextends from more than a week toless than 7 years.2,3

Routes of Exposure

For humans, there are three primaryroutes of exposure: inhalation (bybreathing); oral (by eating or drink-ing); and dermal (through the skin).2,4

Inhalation exposure can be acute,for example breathing a chemical dur-ing short-term use, or chronic, for ex-

ample longer-term inhalation of chemi-cals in an indoor environment.5

Oral exposure can be direct (eatingor drinking) or indirect such as fromhand to mouth contact after touchinga chemical. It can also be either acuteor chronic.5

Dermal exposure is usually short-term from splashing or spilling thechemical during use or from contact

with treated surfaces. I t can result indamage to the skin or absorptionthrough the skin into the body.Dermal exposure can also be chronicif it occurs repeatedly over a long

Megan Kemple is NCAPs public education

coordinator.

period of time.5

A minor route of exposure is ocu-lar (through the eye).4 Ocular expo-sure is also usually short term andresults from splashing or spilling thechemical during use or from rubbing

the eye with contaminated hands aftertouching treated surfaces.5

Health Effects

Commonly studied health effectsfrom chemical exposure include theability to cause cancer (carcinogenic-ity), effects on organs, reproductiveeffects, and developmental effects.Lung cancer, skin cancer, leukemia,breast cancer, and prostate cancer haveall been associated with chemical ex-posure. Reproductive effects involve adecrease or loss of fertility. Develop-

mental effects are those that lead todeath of the fetus (fetotoxicity) orthose that cause birth defects (ter-atogenicity) . Organs often targeted bychemicals include the liver, kidneys,and nervous system.6

Other important health effects in-clude impairment of the immune sys-tem, genetic damage (mutagenicity),and inhibition of the bodys ability tobreak down chemicals.7

Toxicity Measurements

The dose is the amount of expo-sure to a potentially toxic agent and is

Lethal Dose Measurement Versus Acute Toxicity Rating

LOW Lethal Dose =HIGH Toxicity Rating

A high lethal dose means low acute toxicity, and a low lethal dose means high acute toxicity.

MEDIUM Lethal Dose =MEDIUM Toxicity Rating

HIGH Lethal Dose =LOW Toxicity Rating


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JOURNAL OF PESTICIDE REFORM/WINTER 2001 VOL. 21, NO. 4

EPA Reg. No. 62719-260

Precautionary Statements

Hazards to Humans and Domestic AnimalsKeep Out of Reach of Children

CAUTION PRECAUCIONPrecaucion al usuario: Si usted no lee ingls, no use este productohasta que la etiqueta le haya sido explicada ampliamente.

It is a violation of Federal law to use this product in awith its labeling.Read all Directions for Use carefully before applying.

This product may not be applied to forage that is t

for commercial purposes.

distributed throughout the body, as ourbodies are largely made of water. If itis fat-soluble it may accumulate inbody fat. Chemicals can also accumu-late in bones or other organs.2

Variability and Susceptibility

How the body responds to expo-sure to chemical exposure depends agreat deal on the individual. Certainpopulations of people are generallymore sensitive, including the youngand the old and those with compro-mised immune systems or livers. Malesand females may respond differentlyto chemical exposures and are at riskfor different health effects. Somepeople are more susceptible to chemi-cal exposure and more likely to sufferhealth effects because of their geneticmake-up.2 People with previous chemi-cal exposure may be more sensitiveto exposure to the same chemical orother chemicals in the future.5

Summary

The adverse effects of a chemicaldepend on its toxicity, how peopleare exposed to the chemical, and eachpersons individual susceptibility. Ex-posure to chemical agents can lead toa wide range of health effects whichmay be expressed immediately or take

years to develop. The toxicity ratingson pesticide labels are limited in that

they refer only to acute toxicity.Scientific journals, government

documents, and the media all provideinformation about specific health ef-fects associated with exposure to pes-ticides. A basic understanding of toxi-cology terms will help you understandthese materials and use them to helpreduce pesticide use in your commu-nity. Need more details? NCAP canhelp. Call or e-mail us!

Megan Kemple

References

1. Lu, F.C. 1996. Basic toxicology: Fundamentals,target organs, and risk assessment. Washing-ton, D.C.: Taylor & Francis., p. 3.

2. Gilbert, S.G. 2001. An introduction to toxicol-ogy. A lecture given at A Small Dose of Toxi-cology: How Chemicals Affect Your Health, aconference sponsored by the Northwest Centerfor Occupational Safety and Health, Universityof Washington, Oct. 17.

3. Stelljes, M.E. 2000. Toxicology for non-toxicolo-gists. Rockville, MD: Government Institutes. p.28-29.

4. Ref. # 3, p. 25-27.

5. Dickey, P. 2001. Toxicity of common householdproducts. A lecture given at A Small Dose ofToxicology: How Chemicals Affect Your Health,a conference sponsored by the Northwest Cen-ter for Occupational Safety and Health, Univer-sity of Washington, Oct. 17.

6. Ref. # 3, p. 39-51.

7. Ponce, R. 2001. How chemicals attack cells. Alecture given at A Small Dose of Toxicology:How Chemicals Affect Your Health, a confer-ence sponsored by the Northwest Center forOccupational Safety and Health, University ofWashington, Oct. 17.

8. 40 Code of Federal Regulations156.10(h)-(i).

usually measured in milligrams per ki-logram (mg/kg), or mg per liter (mg/l)

where mg is the amount of chemicalpresent, kg refers to the weight of theperson or animal exposed and l is aliter of air.5 The toxicity of chemicals

is often measured using what is calledan LD50 (lethal dose) or an LC50 (le-thal concentration). The LD50 and theLC50 refer to the dose that producesdeath in half of the test animals2 (usu-ally rats and mice). A high LD50 orLC50 implies a lower toxicity becausemore of the chemical is required toresult in death. A low LD50 or LC50implies a higher toxicity; just a smallamount of the chemical results in deathof 50 percent of the population beingtested.2 Both the LD50 and LC50 mea-sure acute effects, and therefore pro-

v ide no information about achemicals connection to chronic(long-term) health effects. Anotherproblem with using LD50s or LC50s asa measure of toxicity is that when re-searchers calculate them they usuallydo so based on exposure to only onechemical, yet in the real world weare not exposed to only one chemicalat a time.2

The Environmental ProtectionAgency (EPA) requires that pesticideproducts be labeled with a signal word(danger, warning or caution). The sig-nal words refer to toxicity categoriesestablished by the EPA. There are 4categories, with I (danger) being themost toxic and III or IV (caution) be-ing the least toxic. EPA assigns pesti-cide products toxicity categories basedon five acute toxicity tests.8 Like theLD50 or LC50, they do not provide in-formation about many other effects

which are associated with exposure topesticide products. (See Signal Wordson Pesticide Labels Are Based onLimited Information, this page.)

Metabolism and Distribution

Metabolism refers to how the bodybreaks down a chemical, what thechemical turns into in the body, andhow fast the chemical is processed. Inpeople, the primary organ for breakingdown chemicals is the liver.

Distribution describes where thechemical accumulates in the body. Ifa chemical is water-soluble it will be

Does not consider:

cancerbirth defectsreduced fertilitydamage to the immune systemgenetic damagedamage to organ systemseffects on hormone systemsdamage to the nervous systeminteractions with other chemicals

Only based on:

acute oral toxicityacute inhalation toxicityacute dermal toxicityeye irritationskin irritationskin allergies

Signal Words (Danger, Warning, Caution) on Pesticide LabelsAre Based on Limited Information

The signal word on a pesticide label is based only on acute toxicity tests.


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JOURNAL OF PESTICIDE REFORM/SPRING 2002 VOL. 22, NO. 1

S K I L L S

It might seem unlikely that a 16thcentury physician and alchemist whomade his reputation by publicly burn-ing classical medical books could beat the foundation of our pesticide regu-latory system, but many pesticide ac-tivists have heard his writing repeat-edly quoted by those who seek tominimize pesticide hazards.

This article will explain what con-

nects this scholar from 500 years agoto current pesticide use, and how pes-ticide activists can best respond to thearguments from pesticide proponentsbased on his ideas.

Paracelsus

Paracelsus was born in Switzerlandin 1493. Among his many accomplish-ments, he wrote the best clinical de-scription of syphilis (of his day); un-derstood that miners silicosis wascaused by breathing in minerals and

was not a punishment for sins; andrefused to accept the value of the pillsand salves used as medicine at thattime.1 He also wrote, All things arepoison and nothing is without poison.Solely the dose determines that a thingis not a poison.2 Now called the dose-

ABCSOF TOXICOLOGY, PART 2:

DOSEAND RESPONSE

Caroline Cox is JPRs editor.

quoted sentences, the dose-responsecurve that is used in standard pesti-cide risk assessments (except for somecancer-causing pesticides)5 has two im-portant features. (See Figure 1.) First,it has a threshold. Below this thresh-

old dose, no response can be mea-sured.5 Second, the response increases

with increasing dose until it reachesmaximum effects and then doesnt in-crease any more.3

How Does Pesticide

Regulation Depend on Dose-

Response Relationships?

Pesticide regulation today assumesthat almost all pesticides fit the rela-tionship described above. In particu-lar, the U.S. Environmental Protection

Agency (EPA) and the other agencies

and institutions that conduct pesticiderisk assessments in general assume thatthey can identify a threshold dose orexposure. Exposures below this thresh-old are safe, and do not cause prob-lems. The setting of acceptable con-tamination levels on food (tolerances)as well as decisions about registeringparticular uses of a pesticide are madeusing this threshold concept.6,7

Whats Changed Since

Paracelsus?

Modern toxicology has shown thatthe standard pesticide dose-responserelationship doesnt represent the com-plexities of interactions with toxicchemicals. Pesticide regulation hasntkept up with these changes, but theyreimportant! Recent significant advancesinclude the following concepts:

Allergies: The shape of a dose-re-sponse relationship for allergic re-

Figure 1Dose-Response Relationships

Sources: Ref. # 3, 4, and 13.

BeckerMedicalLibrary,Wash

ingtonUniv.SchoolofMedicine,St.Louis

response relationship, that concept hasbecome the principle on which thescience of toxicology is based.3

What Is a Dose-Response

Relationship?A dose-response relationship de-

fines the potency of a chemical.4 Inother words, it describes how achemicals effects (on people, labora-tory animals, wildlife, etc.) change asexposure to the chemical increases.

Although Paracelsus did not specifyany quantitative details in his often-

Response

Dose

Standard model used to

regulate pesticides

Dose

Response

Non-threshold relationship Inverted relationship

Dose

Response


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JOURNAL OF PESTICIDE REFORM/SPRING 2002 VOL. 22, NO. 1

Summing UpPesticide regulation needs to be

based on good science, making con-tinuous use of current research andthe increased understanding that comes

with it. By insisting that only an old

and simplistic dose-response relation-ship can be relevant to pesticides, pes-ticide proponents are hiding from mod-ern toxicology. Five hundred years ago,Paracelsus was actually searching fornewer and better ways to understandhow chemicals interact with the hu-man body, not accepting obsoleteideas. Pesticide regulation today needsto follow his example.Caroline Cox

References

1. Paracelsus. Encyclopedia BritannicaOnline.1998. Paracelsus. www.search.eb.com/topic?artcl=58368&seq_nbr=1&page=n&isctn=2&pm=1.

2. Goodman, J.L. 1998. The traditional toxicologicparadigm is correct: Dose influences mechanism.Environ. Health Persp. 106 (Suppl. 1): 285-288.

3. Extension Toxicology Network. 1993. Dose-re-sponse relationships in toxicology. http://ace.orst.edu/info/extoxnet/tibs/doseresp.htm.

4. S tel l jes , M.E. 2000. Toxicology for non-toxicologists. Rockville MD: Government Insti-tutes. Pp. 33-37.

5. U.S. EPA. Integrated Risk Information System.1999. Glossary of IRIS terms. www.epa.gov/iris/gloss8.htm. (Definitions for reference dose andthreshold.)

6. U.S. EPA. Office of Pesticide Programs. 1999.Assessing health risks from pesticides.www.epa.gov/opp00001/citizens/riskassess.htm.

7. U.S. EPA. Office of Pesticide Programs. Undated.Setting tolerances for pesticide residues in foods.

www.epa.gov/pesticides/citizens/stprf.htm.8. Kreutzer, R., R.R. Neutra, and N. Lashuay. 1999.Prevalence of people reporting sensitivities tochemicals in a population-based survey. Am. J.Epidemiol. 150:1-12.

9. Axelrod, D. et al. 2001. Its time to rethink dose:The case for combining cancer and birth anddevelopmental defects. Environ. Health Persp.109: A 246-A 249.

10. Daniels, J.L. et al. 2001. Residential pesticide ex-posure and neuroblastoma. Epidemiol. 12: 20-27.

11. Federal Food, Drug, and Cosmetic Act 408(b)(2)(C).12. Leng, G. and J. Lewalter. 1999. Role of indi-

vidual susceptibility in risk assessment of pesti-cides. Occup. Environ. Med. 56: 449-453.

13. Sheehan, D.M. et al. 1999. No threshold dosefor estradiol-induced sex reversal of turtle em-bryos: How little is too much? Environ. HealthPersp. 107: 155-159.

14. Slotkin, T.A. et al. 2001. Persistent cholinergicpresynaptic deficits after neonatal chlorpyrifosexposure. Brain Res. 902: 229-243.

15. Bigsby, R. et al. 1999. Evaluating the effects ofendocrine disruptors on endocrine function dur-ing development. Environ. Health Persp. 107(Suppl. 4): 613-618.

16. Takai, Y. et al. 2001. Preimplantation exposureto bisphenol A advances postnatal development.Repro. Toxicol. 15: 71-74.

17. Markey, C.M. et al. 2001. In utero exposure tobisphenol A alters the development and tissueorganization of the mouse mammary gland. Biol.Repro. 65: 1215-1223.

sponses can be completely differentfrom the standard curve.3 People whoare allergic to a particular substancecan have a significant reaction to evena tiny exposure. Allergies to pesticideshave not been well studied, but a sur-

vey in California indicates that theyseem to be surprisingly common.Californias Department of Health Ser-

vices found that almost 16 percent ofCalifornians reported that they wereallergic or unusually sensitive to ev-eryday chemicals.8

Special susceptibility of children:The standard pesticide dose-responsecurve fails to recognize the exquisitesensitivity9 of fetuses, babies, and chil-dren. Their organ systems are devel-oping and their exposure to chemi-cals, for their size, can be higher than

adults.8 For example, a new study fromthe Childrens Cancer Group linkschildrens brain cancers with exposureto pesticides before birth or duringchildhood.10 This is a response that

would be entirely missing from thestandard dose-response relationshipbased on testing of adult laboratoryanimals. In 1996, Congress authorizedEPA to use an additional tenfold mar-gin of safety11 to protect children, butotherwise left intact the use of thestandard dose-response relationship.

Individual ability to detoxifypesticides: Every person is different,but the use of standard dose-responserelationships omits these individual dif-ferences. For example, a study of

workers at a Bayer AG facility whohandled insecticides found that in cer-tain individuals detoxification occurredslowly. These individuals more oftenshowed signs of pesticide poisoningthan individuals whose bodies wereable to quickly remove the pesticide.For some of the pesticides studied,about half of the workers studied hadslow detoxification abilities.12

Response relationships withouta threshold: Not all dose-responserelationships have thresholds.4 Thismeans that there is not a dose that istoo low to exert adverse effects.13 Forexample, a U.S. Food and Drug Ad-ministration study of hormone disrup-tion in turtles found that every dosetested of the hormone estradiolchanged the sex ratio. The lowest dose

was minuscule, 400 trillionths of a gramper egg. The scientists who conductedthe study concluded that similar non-threshold dose-response relationships

will be frequently encountered.13An-other example is the insecticidechlorpyrifos; scientists from Duke Uni-

versity have found developmental ef-fects at low doses that cause no overtsigns of toxicity.14

Inverted dose-response relation-ships: In the standard pesticide dose-response relationship, responses in-crease as dose increases. However,some chemicals have an inverted rela-tionship and higher doses of thechemical actually inhibit some re-sponses that are stimulated by muchlower doses.15 Examples come fromrecent studies of bisphenol A, used inplastics and as an inert ingredient inpesticides. At environmentally rel-evant16,17 concentrations, bisphenol Achanged the developmental rate ofmouse embryos16 and altered the struc-ture of breast tissue in adolescent micein a way that is associated with breastcancer.17 In both cases, researchersfound that low doses had a greatereffect than the higher doses.

By insisting that only

an old and simplistic

dose-response rela-

tionship can be rel-

evant to pesticides,

pesticide proponents

are hiding from

modern toxicology.

USDA/DougWilson

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