Clinical Toxicology, 38(4), 389–394 (2000)

Efficacy of the Cation Exchange Resin,Sodium Polystyrene Sulfonate, to DecreaseIron Absorption

Greene Shepherd; Wendy Klein-Schwartz; Aaron H. Burstein

Maryland Poison Center, Baltimore, Maryland (GS, WK-S); University ofMaryland School of Pharmacy (AHB)

ABSTRACT

Background: Iron is not bound by charcoal; therefore, a method of bindingiron in the gastrointestinal tract to prevent absorption in iron overdose isneeded. This study investigated the efficacy and safety of sodium polystyrenesulfonate to prevent absorption of iron in human volunteers. Methods: Six adultvolunteers completed this prospective crossover trial. Following an oral doseof elemental iron 10 mg/kg, each subject received sodium polystyrene sulfonate30 g or water as control. Baseline and serial serum iron samples were drawnto determine pharmacokinetic parameters. Results: A trend toward increasedtime to peak following sodium polystyrene sulfonate compared to the controlarm (5.7 vs 3.6 hours) was observed but was not statistically significant (p 50.517). A trend toward smaller area-under-the-curve for the sodium polysty-rene sulfonate was evident but was not statistically significant (p 5 0.77). Ironconcentration increased on average 298 mcg/dL and 370 mcg/dL above base-line in the treatment and control arms (p 5 0.44). Sodium polystyrene sulfonateis not an effective method of decontamination for iron overdose.

Correspondence: Dr. Greene Shepherd, North Texas Poison Center, 5201 Harry Hines Blvd., Dallas, TX 75235. Tel: 214/589-0911;Fax: 214/590-5008; E-mail: gsheph@parknet.pmh.org

389

Copyright 2000 by Marcel Dekker, Inc. www.dekker.com

Clin

ical

Tox

icol

ogy

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

Uni

vers

ity o

f C

alif

orni

a Ir

vine

on

10/2

9/14

For

pers

onal

use

onl

y.

ORDER REPRINTS

390 Shepherd, Klein-Schwartz, and Burstein

INTRODUCTION

Iron overdoses in young children can result in seriousinjury and death. Analysis of life-threatening and fatalpediatric poisonings reported to poison centers found ironto be the most frequent cause of pediatric unintentionalingestion fatalities.1 In response to the large number ofiron poisonings and poisoning deaths, the FDA issuedregulations requiring label warning statements and unitdose packaging for products containing 30 mg or moreof iron per dosage unit.2

A goal of managing patients following an overdose isto prevent or minimize absorption of the ingested sub-stance. Controversy exists regarding the optimal methodof limiting absorption in the iron-poisoned patient. Gas-tric emptying with ipecac syrup in the alert patient andwith gastric lavage in the obtunded patient have been rec-ommended. Ipecac syrup–induced vomiting may maskthe early phase of gastrointestinal (GI) symptoms associ-ated with iron and is potentially harmful to patients withgastric injury from iron. Numerous lavage solutions havebeen proposed to complex the iron in the GI tract; nonehave proven efficacious and some have demonstrated sig-nificant toxicity.3–5 In addition, the efficacy of lavage islimited in children because of the small lumen of thetubes used in this population. Activated charcoal, themainstay of GI decontamination for the poisoned patient,does not adsorb iron. Whole-bowel irrigation may be ef-fective but is not universally practiced.6

Alternative GI decontamination procedures specifi-cally for iron intoxications warrant investigation. Re-cently, interest has been generated in the potential use ofthe cation exchange resin, sodium polystyrene sulfonate(SPS), for cations such as lithium and iron, which are notadsorbed by activated charcoal.7–11 An in vitro studyfound that SPS was very effective at binding iron.7

The purpose of this study was to investigate the effi-cacy and safety of SPS at preventing iron absorption inhuman volunteers.

METHODS

The study was a prospective, unblinded, randomizedcrossover trial in adult volunteers. The InvestigationalReview Boards at the University of Maryland MedicalSystem and the Baltimore Veterans Administration Hos-pital approved the study.

Six normal, healthy, adult volunteers entered into thestudy. A sample size of 6 was determined based on αof 0.05, β of 0.20, and an expected difference of 50%

(pharmacokinetic parameter value coefficient of variation% of 30) in area-under-the-iron serum concentration timecurve and/or maximal concentrations. Healthy men andwomen between the ages of 18–45 years were eligible toparticipate in the study. All subjects completed a medicalquestionnaire and gave informed consent prior to partici-pating in the study. Exclusion criteria included hemato-logic abnormalities, low serum iron, hypertension, car-diac disease, thyroid abnormalities, renal disease,diabetes, hypokalemia, sodium disorders, and/or con-comitant use of any medication except oral contracep-tives. Pregnant women and women not using birth controlwere also excluded.

Subjects fasted overnight before each arm of thestudy. The study was conducted in the Clinical ResearchUnit (CRU) at the Baltimore Veterans AdministrationHospital. Baseline laboratory tests obtained before eachstudy arm included serum iron concentrations (photomet-ric analysis based on the Ferrozine method without de-proteinization: Roche Diagnostics Corporation, India-napolis, IN), complete blood counts (repeated at 24hours), and electrolytes to assess serum potassium (chem7; also drawn at 4 and 24 hours after the iron dose). Se-rum potassium outside the range of 3.5–5 mEq/L wasconsidered abnormal. Subjects were randomized to eitherthe treatment or control protocol in the first arm of thestudy. After a washout period of at least 10 days, subjectsreceived the opposite protocol in the second arm of thestudy. The study was started at the same time in the morn-ing for both arms of the study, in which subjects receivedelemental iron 10 mg/kg in the form of 325-mg ferroussulfate tablets (65 mg of elemental iron per tablet; UnitedResearch Laboratories, Inc., Philadelphia, PA), roundedto the nearest whole tablet.

In the treatment arm, the dose (FE) was followed 45minutes later by SPS 30 g (FE/SPS) (Kayexalate, SanofiWinthrop Pharmaceuticals, New York, NY) mixed witha 70% sorbitol solution (Paddock Laboratories, Inc.,Minneapolis, MN). In the control arm, subjects receivedthe same iron dose followed by a volume of water equalto the volume of SPS (120 mL). Serial serum iron levelswere drawn before ingestion and at 0.5, 1, 1.5, 2, 3, 4,8, and 24 hours after ingestion of iron. Subjects fastedfor 4 hours after the iron dose, although a few crackersand small sips of ginger ale were allowed as needed fornausea and vomiting. After the 4-hour blood draws, sub-jects received a standard lunch.

CRU personnel documented adverse events occurringduring the first 8 hours. Subjects were given an adverseevent reporting form to document any adverse events thatoccurred after leaving the CRU.

Clin

ical

Tox

icol

ogy

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

Uni

vers

ity o

f C

alif

orni

a Ir

vine

on

10/2

9/14

For

pers

onal

use

onl

y.

ORDER REPRINTS

Efficacy of SPS to Prevent Iron Absorption 391

Noncompartmental techniques were used to analyzethe iron serum concentration time profiles.12 Serum ironconcentrations at each time point were transformed to achange from baseline (time zero) for each treatment. Thismethod has been found to be as effective comparing toserial baseline values.13 Maximal change in serum ironconcentration from baseline (Cmax) and time to maximalpercent change in serum iron concentration from baseline(Tmax) were determined directly from inspection of thegraphical profiles. Area-under-the-curve (AUC) fromtime zero (pre-dose) to the time of the last detectedplasma concentration (AUClast) was determined by lineartrapezoidal summation (WinNonlin V1.1, Scientific Con-sulting, Inc., Apex, NC).

Statistical analyses were performed using the SystatVersion 7.0 (SPSS Inc., Chicago, IL) software. Pharma-cokinetic parameter values following FE and FE/SPStreatments were compared using a 2-way analysis of vari-ance (ANOVA) incorporating factors of treatment, pe-riod, and sequence. Baseline iron concentrations prior totreatment during periods 1 and 2 were compared using apaired Student’s t-test. For all tests, significance was de-fined as a p value of 0.05 or less.

RESULTS

Eight subjects were recruited for the study. Two sub-jects were excluded because of low baseline serum ironconcentrations. Six subjects, 3 women and 3 men, com-pleted the study. The pharmacokinetic variables are sum-marized in Table 1. Serum iron concentration-time datafor the SPS and control groups are shown in Figure 1.No difference in baseline iron concentration prior to thefirst (99.7 mcg/dL) and second (102.8 mcg/dL) study pe-

Table 1

Pharmacokinetic Variables

AUC (mcg/h/dL) Dmax (mcg/dL) Tmax (h)

Subject FE FE 1 SPS FE FE 1 SPS FE FE 1 SPS

1 5620 4162 376 264 8 82 8360 5108 563 407 4 83 4938 5132 411 384 4 44 3852 3648 314 266 1.5 85 3278 2443 245 220 2 46 2482 2859 313 248 2 2

Mean 4755 3892 370 298 3.6 5.7SD 2095 1124 110 77.5 2.4 2.7

Figure 1. Serum concentration–time curves for iron andiron 1 SPS.

riods was detected. A trend toward a longer time to peakiron concentration following the SPS compared to thecontrol arm (5.7 vs 3.6 hours) was noted. However, thisdifference did not attain statistical significance (p 50.517). A trend toward smaller AUC for the SPS com-pared to the control arm (3892 vs 4755 mcg/h/dL) wasevident, although this difference failed to achieve statisti-cal significance (p 5 0.77). Following SPS, the serumiron concentration increased on average of 298 mcg/dLabove baseline. In the control group there was an averageincrease of 370 mcg/dL in serum iron concentration.

Clin

ical

Tox

icol

ogy

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

Uni

vers

ity o

f C

alif

orni

a Ir

vine

on

10/2

9/14

For

pers

onal

use

onl

y.

ORDER REPRINTS

392 Shepherd, Klein-Schwartz, and Burstein

Table 2

Serum Potassium Following SPS Administration

Serum Potassium (mEq/L)

24Subject Baseline 4 Hours Hours

1 3.8 5.6* 3.62 4 4 4.13 4 4.1 4.44 4.4 4.2 45 3.8 3.8 4.26 3.6 4 3.9

* Partially hemolyzed sample.

These differences in Cmax were not significant (p 50.408).

In both arms of the study electrolytes, glucose, andCBC did not significantly change from baseline and werewithin normal ranges. Serum potassium concentrationswere not decreased by the administration of SPS (Table2). Adverse effects in the treatment arm included nausea(n 5 6), vomiting (n 5 3), and diarrhea/loose stool (n 56). In the control arm adverse effects included nausea(n 5 5), vomiting (n 5 2), stomach cramps (n 5 1),and diarrhea/loose stool (n 5 2). There were no tabletfragments observed in the vomitus.

DISCUSSION

GI decontamination is part of the standard regimenfor managing patients with potentially toxic ingestions.While activated charcoal is the primary method of GIdecontamination for most toxins, it is ineffective for cer-tain substances including mineral acids, alkaline corro-sives, alcohols, aliphatic hydrocarbons, lithium, andiron.14–19 Iron is poorly bound because of its small size.Phosphate or bicarbonate lavage solutions do not ade-quately complex iron to prevent absorption; phosphatelavage solutions have resulted in hyperphosphatemia andhypocalcemia.3–5 The iron-chelating agent deferoxaminehas been shown to increase iron absorption when admin-istered orally.20 A recent human volunteer study has dem-onstrated significant decreases in iron absorption whenactivated charcoal and deferoxamine are combined in a3:1 ratio.21 Limitations of this study include the relativelylow dose of iron (10 mg/kg) which was administered insolution with the complexing agents mixed in prior toadministration. Because most iron overdoses involve in-gestions of tablets and there is a delay between ingestion

and initiation of GI decontamination procedures, thisdoes not simulate the clinical situation. Another recentstudy examined the effects of magnesium hydroxide oniron absorption. This study found that iron absorptioncould be significantly decreased by the administration of4.5 g of magnesium hydroxide for every gram of ironingested.22 The clinical relevance of this study is limitedby the subtoxic dose and the possibility of toxicity fromlarge doses of magnesium hydroxide. Because there isclearly no standard iron complexing agent for GI decon-tamination, other modalities warrant investigation.

SPS is a cationic binding resin that was developed inthe 1960s to facilitate removal of excess serum potas-sium.23 Recent studies investigating binding of lithium toSPS in vitro as well as its utility in facilitating the re-moval of lithium in intoxicated patients have shown somebenefit.7–11 Iron, like lithium, is a cation which is not ad-sorbed by activated charcoal.14,16

In vitro experiments investigating the ability of SPSto bind iron from ferrous sulfate solutions found almostcomplete binding at a ratio of 3.5 g of SPS to 65 mg ofelemental iron.7 These investigators demonstrated 98%binding at a pH of 2 and 95% binding at a pH of 7. There-fore, a ratio of 54:1 (SPS to iron) should produce nearlycomplete binding at a pH of 2. This suggests that SPSmight be clinically useful in preventing iron absorptionfollowing a potentially toxic ingestion. In our study ironto SPS ratios ranged from 55:1 to 29:1; this would pre-dict binding between 98% and 54% of the ingested iron.However, we were unable to demonstrate significantbinding of iron in vivo.

This study was designed so that the dose of iron andthe dose of SPS delivered 45 minutes after the iron wouldapproximate the doses involved in a significant pediatriciron exposure. The SPS dose of 30 g has been previouslyused in human volunteer studies of lithium absorption aswell as in the management of a lithium overdose.10,11 Inoverdose patients, the exact dose of the ingested toxin isoften unknown making it difficult to dose an adsorbentsuch as activated charcoal or a complexing agent such asSPS based on the dose of toxin. For example, with acti-vated charcoal the dose is usually not based on theamount of toxin, but rather based on patient weight (1 g/kg) or an absolute dose (50–100 g in adults and 15–30g in children).

Experience with SPS and lithium in a total of 17 sub-jects and with iron in our 6 subjects found efficacy lessthan predicted by in vitro models.8–10 A possible explana-tion for the lack of effect of SPS in vivo is preferentialbinding of potassium from the gut instead of the iron.The amount of potassium removed by a 30-g dose of SPSwould not affect the serum concentration due to extensive

Clin

ical

Tox

icol

ogy

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

Uni

vers

ity o

f C

alif

orni

a Ir

vine

on

10/2

9/14

For

pers

onal

use

onl

y.

ORDER REPRINTS

Efficacy of SPS to Prevent Iron Absorption 393

intracellular stores. Alternatively, it may be postulatedthat the iron was initially bound by the SPS but later un-derwent desorption in the alkaline milieu of the smallintestine. Based on in vitro data,7 and assuming reversiblebinding/complexation of FE and SPS, it could be ex-pected that SPS would efficiently bind the iron in the lowpH environment of the stomach. Upon entrance into themore alkaline small intestine, desorption of iron from theSPS may have occurred. This initial binding followed bydesorption would partially explain the trend in longerTmax seen in the SPS treatment group.

The dose of 10 mg/kg of elemental iron was consid-ered safe because it is lower than the usual minimal toxicdose.24 In other human volunteer studies iron has beenused in doses ranging from 5 to 20 mg/kg. A ferroussulfate absorption study in 6 volunteers reported nausea(2/6), diarrhea (1/6), and dark stool (2/6).24 Nausea andlightheadedness occurred in 7 male volunteers following5 mg/kg of iron elixir.8 Mild nausea, diarrhea, and head-ache occurred in 5 volunteers receiving 5 and 10 mg ofiron in a multivitamin preparation.18 In a total iron-bind-ing capacity study using a dose of elemental iron 20 mg/kg, all 6 subjects experienced nausea, abdominal cramps,and voluminous diarrhea.26 One subject vomited twice. In2 other studies 5 of 24 subjects experienced mild transientnausea without emesis after 5 mg/kg of ferrous sul-fate.21,22

Nausea and vomiting were frequent adverse effects inour study. All 6 subjects experienced some degree of nau-sea and 3 experienced vomiting. It is conceivable thatsome of the GI symptoms were caused by the SPS andsorbitol solution. Subjects treated with lithium and SPSalso experienced GI problems. In one study 2 of 6 SPSsubjects and 1 of 6 control subjects experienced nausea.9

In another study 5 of 11 subjects experienced abdominalcramping and/or diarrhea during SPS treatment.10

To adequately characterize absorption and peak con-centrations, 6 serum iron concentrations were obtainedwithin the first 4 hours after iron dosing. This blood sam-pling schedule was based on evidence for a peak serumiron concentration within 2–4 hours after ingestion ofimmediate release iron preparations.13,27 Because a trendtoward delayed iron absorption following SPS was ob-served, additional serum iron concentration measure-ments between 4 and 8 hours would have allowed for amore accurate characterization of maximal concentra-tions in this model. Other limitations in the study designthat are inherent to human volunteer studies are less im-portant considering our negative findings.

The iron dose of 10 mg/kg is supertheraputic but sub-toxic. The SPS to iron ratios achieved in this study wouldbe difficult to obtain in an adult iron overdose. The SPS

was administered only 45 minutes after the iron overdosewhile in the clinical situation adults often present to theemergency department several hours after the overdose.The control arm used 120 mL of water rather than 120mL of 70% sorbitol solution. Because it was ineffectivein this ‘‘ideal’’ situation, it is even less likely that SPShas any role in the clinical situation.

This study lacked adequate power to detect significantdifferences based on the findings described herein. Asample size of 6 subjects was determined based on a pri-ori assumptions regarding the magnitude of effect antici-pated and the variability in parameter values in the ironalone control group. Post hoc sample size calculationsdetermined that with the magnitude of effect observed,12 subjects, 20 subjects, and 48 subjects would need tohave been evaluated to demonstrate statistically signifi-cant differences for Tmax, Cmax, and AUC, respectively.

In summary, our findings in human subjects contrastmarkedly with in vitro findings and suggest that SPS isnot an effective method of preventing iron absorption.The dose of 10 mg/kg of elemental iron produced sig-nificant GI symptoms. The study found trends toward de-layed absorption, lower Cmax, and smaller AUC with theadministration of SPS, but these were not statistically sig-nificant. It is unlikely that these differences could proveto be clinically significant, suggesting that SPS would notbe useful in preventing iron absorption.

ACKNOWLEDGEMENTS

This study was presented at the 1998 North American Con-gess of Clinical Toxicology in Orlando, Florida on September10–15, 1998.

It was funded in part by the Texaco-AACT fellowshipaward.

REFERENCES

1. Litovitz TL, Manoguerra A. Comparison of pediatric haz-ards: An analysis of 3.8 million exposure incidents. Areport from the American Association of Poison ControlCenters. Pediatrics 1992;89:999–1006.

2. Iron containing supplements and drugs: Label warningstatement and packaging requirements: Final rule. Fed-eral Register 1997;62:2217–2250.

3. Greffner ME, Opas LM. Phosphate poisoning complicat-ing treatment for iron ingestion. Am J Dis Child 1980;134:509–510.

4. Czajka PA, Konrad JD, Duffy JP. Iron Poisoning: An invitro comparison of bicarbonate and phosphate lavage so-lutions. J Pediatr 1981;98:491–494.

5. Bachrach L, Correa A, Levin R, et al. Iron poisoning and

Clin

ical

Tox

icol

ogy

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

Uni

vers

ity o

f C

alif

orni

a Ir

vine

on

10/2

9/14

For

pers

onal

use

onl

y.

ORDER REPRINTS

394 Shepherd, Klein-Schwartz, and Burstein

complications of hypertonic phosphate lavage therapy. JPediatr 1979;94:147–149.

6. Tenenbien M. Whole bowel irrigation in iron poisoning.J Pediatr 1987;111:142–145.

7. O’Connor TA, Gruner BA, Gehrke JC, Watling SM, Geh-rke CW. In vitro binding of iron with the cation exchangeresin sodium polystyrene sulfonate. Ann Emerg Med1996;28:504–507.

8. Watling SM, Gehrke JC, Gehrke CW, Zumwalt R, Prib-ble J. In vitro binding of lithium using the cation ex-change resin, sodium polystyrene sulfonate. Am J EmergMed 1995;13:294–296.

9. Gehrke JC, Watling SM, Gehrke CW, Zumwalt R. In vivobinding of lithium using the cation exchange resin, so-dium polystyrene sulfonate. Am J Emerg Med 1996;14:37–38.

10. Belanger DR, Tierney MG, Dickinson G. Effect of so-dium polystyrene sulfonate on lithium bioavailability.Ann Emerg Med 1992;21:1312–1315.

11. Roberge RJ, Martin TG, Scheneider SM. Use of sodiumpolystyrene sulfonate in a lithium overdose. Ann EmergMed 1993;22:1911–1915.

12. Non-compartmental analysis. In: Pharmacokinetic andPharmacodynamic Data Analysis: Concepts and Appli-cations, 2nd Ed. Gabrielson J, Weiner D, eds., Stock-holm, Sweden: Swedish Pharmaceutical Society, Swed-ish Pharmaceutical Press 1997.

13. Walker SE, Paton TW, Cowan DH, Manuel MA, Dranits-aris G. Bioavailibility of iron in ferrous sulfate prepara-tions in healthy volunteers. Can Med Assoc J 1989;141:543–547.

14. Decker WJ, Combs HF, Corby DG. Adsorption of drugsand poisons by activated charcoal. Toxicol Appl Pharma-col 1968;13:454–460.

15. Oderda GM, Klein-Schwartz W, Insley BM. In vitrostudy of boric acid and activated charcoal. J Toxicol ClinToxicol 1987;25:13–19.

16. Favin FD, Klein-Schwartz W, Oderda GM, Rose SR. Invitro study of lithium carbonate adsorption by activatedcharcoal. J Toxicol Clin Toxicol 1988;26:443–450.

17. Picchioni AL. Activated charcoal, a neglected antidote.Ped Clin N Am 1970;17:535–543.

18. Andersen AH. Experimental studies on the pharmacologyof activated charcoal. I. Adsorption power of charcoal inaqueous solutions. Acta Pharmacol 1946;2:69–78.

19. North DS, Thompson JD, Peterson CD. Effect of acti-vated charcoal on ethanol blood levels in dogs. Am JHosp Pharm 1981;38:864–866.

20. Jackson TW, Ling LJ, Washington V. The effect of oraldeferoxamine on iron absorption in humans. J ToxicolClin Toxicol 1995;33:325–329.

21. Wallace KL, Curry SC, LoVecchio F, Raschke RA. Ef-fects of magnesium hydroxide on iron absorption follow-ing simulated mild iron overdose in human subjects. Aca-demic Emerg Med 1998;5:961–965.

22. Gomez HF, McClafferty HH, Flory D, Brent J, Dart RC.Prevention of gastrointestinal iron absorption by chela-tion from an orally administered premixed deferoxamine/charcoal slurry. Ann Emerg Med 1997;30:587–592.

23. Frohnert PP, Johnson WJ, Mueller GJ, Tauxe WN,McCall JT. Resin treatment of hyperkalemia. II. Clinicalexperience with a cation exchange resin (calcium cycle).J Lab Clin Med 1968;71:840–846.

24. Linakis JG, Lacouture PG, Woolf A. Iron absorptionfrom chewable vitamins iron versus iron tablets: Implica-tions for toxicity. Ped Emerg Care 1992;8:321–324.

25. Ling LJ, Hornfeldt CS, Winter JP. Absorption of ironafter experimental overdose of chewable vitamins. Am JEmerg Med 1991;9:24–26.

26. Burkhart KK, Kulig KW, Hammond KB, et al. The risein the total iron binding capacity after iron overdose. AnnEmerg Med 1991;20:532–535.

27. Chiou WL. Ferrous sulfate bioavailability monograph. JAm Pharm Assoc 1977;17:377–380.

Clin

ical

Tox

icol

ogy

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

Uni

vers

ity o

f C

alif

orni

a Ir

vine

on

10/2

9/14

For

pers

onal

use

onl

y.

Order now!

Reprints of this article can also be ordered at

http://www.dekker.com/servlet/product/DOI/101081CLT100100948

Request Permission or Order Reprints Instantly!

Interested in copying and sharing this article? In most cases, U.S. Copyright Law requires that you get permission from the article’s rightsholder before using copyrighted content.

All information and materials found in this article, including but not limited to text, trademarks, patents, logos, graphics and images (the "Materials"), are the copyrighted works and other forms of intellectual property of Marcel Dekker, Inc., or its licensors. All rights not expressly granted are reserved.

Get permission to lawfully reproduce and distribute the Materials or order reprints quickly and painlessly. Simply click on the "Request Permission/Reprints Here" link below and follow the instructions. Visit the U.S. Copyright Office for information on Fair Use limitations of U.S. copyright law. Please refer to The Association of American Publishers’ (AAP) website for guidelines on Fair Use in the Classroom.

The Materials are for your personal use only and cannot be reformatted, reposted, resold or distributed by electronic means or otherwise without permission from Marcel Dekker, Inc. Marcel Dekker, Inc. grants you the limited right to display the Materials only on your personal computer or personal wireless device, and to copy and download single copies of such Materials provided that any copyright, trademark or other notice appearing on such Materials is also retained by, displayed, copied or downloaded as part of the Materials and is not removed or obscured, and provided you do not edit, modify, alter or enhance the Materials. Please refer to our Website User Agreement for more details.

Clin

ical

Tox

icol

ogy

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

Uni

vers

ity o

f C

alif

orni

a Ir

vine

on

10/2

9/14

For

pers

onal

use

onl

y.