risk assessment for the carotenoids lutein and lycopene

Regulatory Toxicology and Pharmacology 45 (2006) 289–298

www.elsevier.com/locate/yrtph

Risk assessment for the carotenoids lutein and lycopene �

Andrew Shao ¤, John N. Hathcock

Council for Responsible Nutrition, 1828 L St., NW, Suite 900, Washington, DC 20036-5114, USA

Received 28 March 2006Available online 30 June 2006

Abstract

Lutein and lycopene, two prevalent carotenoids in the human diet have become increasingly popular ingredients in dietary supple-ments. A large body of human and animal research suggests that oral forms of these carotenoids may provide beneWts in the areas of eye,prostate, skin and cardiovascular health. The increased awareness and use of these ingredients in dietary supplements warrants a compre-hensive review of their safety. Systematic evaluation of the research designs and data provide a basis for risk assessment and the usual tol-erable Upper Level of Intake (UL) derived from it if the newer methods described as the Observed Safe Level (OSL) or Highest ObservedIntake (HOI) are utilized. The OSL risk assessment method indicates that the evidence of safety is strong at intakes up to 20 mg/d forlutein, and 75 mg/d for lycopene, and these levels are identiWed as the respective OSL. Although much higher levels have been tested with-out adverse eVects and may be safe, the data for intakes above these levels are not suYcient for a conWdent conclusion of long-term safety.© 2006 Elsevier Inc. All rights reserved.

Keywords: Carotenoids; Lutein; Lycopene; Upper Level of Intake (UL); Observed Safe Level (OSL)

1. Introduction

Of the 600 or so carotenoids that exist in nature, only afraction are consumed in the diet, and of these only a handfulare present in human serum. Lutein and lycopene are amongthe most prevalent carotenoids in the human diet and serum(Johnson, 2002). Their popularity in dietary supplements hassoared in recent years, due in part, to an increase in researchand recent petitions to the Food and Drug Administrationfor the approval of QualiWed Health Claim language (Centerfor Food Safety and Applied Nutrition, 2006).

1.1. Lutein

Lutein, and its stereo isomer zeaxanthin, are lipid-solublemembers of the xanthophyll family of carotenoids (Alves-Rodrigues and Shao, 2004). Lutein is one of the most preva-lent carotenoid in human serum (Khachik et al., 1997), is

� Funding: No funding was speciWc to the production of this manuscript.The salaries for authors were provided by the aYliated organization.

* Corresponding author. Fax: +1 202 204 7980.E-mail address: [email protected] (A. Shao).

0273-2300/$ - see front matter © 2006 Elsevier Inc. All rights reserved.doi:10.1016/j.yrtph.2006.05.007

concentrated in ocular tissues such as the lens and the maculalutea (Yeum et al., 1995; Landrum and Bone, 2001), and ispresent in the human diet primarily in dark, leafy green vege-tables (Holden et al., 1999). Known mostly for its role in eyehealth, consumption and serum levels of lutein have beenshown to be inversely related to the risk for ocular diseases,including age-related macular degeneration (AMD) (EyeDisease Case–Control Study Group, 1993; Seddon et al.,1994; Mares-Perlman et al., 2001), and cataracts (Brownet al., 1999; Chasan-Taber et al., 1999; Lyle et al., 1999; Galeet al., 2001). Findings from a growing collection placebo-con-trolled intervention trials indicate that ingestion of lutein-containing foods or supplements results in increased macularpigment optical density (Johnson et al., 2000; Bone et al.,2003; Richer et al., 2004), and may help to improve visualfunction in patients suVering from AMD and other oculardiseases (Richer, 1999; Dagnelie et al., 2000; Falsini et al.,2003; Olmedilla et al., 2003; Richer et al., 2004).

1.2. Lycopene

Lycopene lacks oxygen atoms and is therefore amember of the hydrocarbon family of carotenoids

mailto: [email protected]

mailto: [email protected]

290 A. Shao, J.N. Hathcock / Regulatory Toxicology and Pharmacology 45 (2006) 289–298

(Khachik et al., 2002) and one of the most prevalentcarotenoid in human serum (Food and Nutrition Board.Institute of Medicine, 2000). Lycopene is present in thehuman diet primarily in dark red fruits and vegetablessuch as tomatoes (Holden et al., 1999), and consumptionand serum levels of lycopene have been linked to areduced risk of cardiovascular disease (Arab and Steck,2000; Willcox et al., 2003) and prostate cancer (Chanet al., 2005; Giovannucci, 2005). Findings from a growingcollection placebo-controlled intervention trials suggeststhat consumption of lycopene (either as a dietary supple-ment or in the form of processed tomatoes) can reduceDNA damage (Astley et al., 2004; Zhao et al., 2006) andmay have beneWcial eVects on prostate cancer (Kucuket al., 2001; Kucuk et al., 2002; Ansari and Gupta, 2003;van Breemen, 2005) and lung cancer (Liu et al., 2003,2006; Wang, 2005).

The increase in both public awareness and usage oflutein and lycopene in dietary supplements warrants a com-prehensive evaluation of their safety. Most upper safe levelsof nutrients and related substances are based on widelyapplicable risk assessment models used by the US Foodand Nutrition Board (FNB) in its Dietary ReferenceIntakes documents in 1997 and after (Food and NutritionBoard. Institute of Medicine, 1997, 1998a,b, 2000, 2001).The FNB method and reviews are a formalization andextension of the quantitative methods widely used earlier inrisk assessment of other substances, and by the food anddietary supplement industries. Because of the systematic,comprehensive and authoritative character of the FNB riskassessment method for nutrients, this approach has gath-ered widespread support and adoption by others such asthe European Commission ScientiWc Committee on Food(SCF) (European Commission, 2001), the United KingdomExpert Group on Vitamins and Minerals (EVM) (FoodStandards Agency, 2003) and more recently by the Foodand Agriculture Organization/World Health Organizationproject report A Model for Establishing Upper Levels ofIntake for Nutrients and Related Substances (FAO/WHO,2006) with some slight modiWcations. All these reportreXect the concepts and procedures established much ear-lier for the risk assessment of non-carcinogenic chemicals(National Research Council, 1983).

2. Methods

The safety evaluation method applied to orally administered lutein orlycopene is from the Council for Responsible Nutrition (CRN) Vitaminand Mineral Safety, 2nd Edition (Hathcock, 2004), which contains thebasic features of the FNB method and also the Observed Safe Level (OSL)modiWcation recently adopted as a Highest Observed Intake (HOI) in theFAO/WHO report.

Overall, this risk analysis was derived from the human clinical trialdatabase through the following major steps:

1. Derive a safe Upper Level of Intake (UL) if the data are appropriate:a. Search for data that identify a hazard related to excessive intakeb. Assess the dose–response relationship for the identiWed hazardc. Consider uncertainty and assign an uncertainty factor (UF)

d. Derive a UL from the No Observed Adverse Intake Level(NOAEL) or Lowest Observed Adverse EVect Level (LOAEL),as ULD NOAEL ¥ UF.

2. If no data establish adverse eVects in humans, the above procedurecannot be used. In these circumstances, the highest intake level is iden-tiWed with suYcient evidence of safety as a value named the OSL byCRN (Hathcock, 2004) and the HOI by FAO/WHO. Uncertainty isconsidered in selection of the OSL value.

We applied the Wrst procedure to the lutein and lycopene human trialdata and found no basis for a NOAEL or LOAEL, and thus could notderive a UL. Consequently, we applied the OSL procedure to the clinicaltrial data, with the results described in the sections below.

No consistent eVorts were made in any of the clinical trials to avoiddietary lutein or lycopene, and therefore the subjects must have been con-suming usual dietary levels of this substance. Thus, the OSL value identi-Wed from the trials does not require correction for dietary intakes, and theOSL can be identiWed as a safe Upper Level for Supplements (ULS).

3. ScientiWc evidence related to safety—lutein

3.1. Human studies

There have been more than thirty peer-reviewed, pub-lished human clinical trials involving lutein. Of these, theeleven most relevant studies regarding safety are presentedin this review (Table 1). Criteria for study inclusion werestudy duration (at least 1 week) and lutein dose utilized(greater than 2 mg/d). Studies investigating acute bioavail-ability, pharmacokinetics or post-prandial responses fromsingle bolus doses were excluded from this analysis, and areused solely as supportive information. Also excluded werestudies that did not quantify the dosage of lutein beingadministered (such as feeding studies). Human trial dataare limited to the use of all-trans lutein, both in the “free”form, and in the fatty acid esteriWed form. Only a few of thestudies undertaken to assess the beneWcial eVects of luteinhave monitored any possible adverse side eVects, and thenprimarily through self-reporting. There are no publishedhuman studies that have focused speciWcally on the safetyof lutein supplementation.

The highest lutein dosage utilized in a human clinicaltrial was 40 mg/d for nine weeks (163 d) followed by anadditional 17 weeks (119 d) at 20 mg/d in retinitis pigmen-tosa patients (Dagnelie et al., 2000). The longest durationtrial was 12 months (365 d) at a lutein dose of 10 mg/d inAMD patients (Richer et al., 2004). Where measured, serumlutein levels increased in a dose-dependent manner. Whileno adverse eVects were observed in any of the reviewedstudies, it should be noted that these trials tended to focuson short term use and did not speciWcally test the eVects ofexposures lasting greater than 12 months.

Mean level of lutein consumption from foods by Ameri-cans is estimated at less than 2 mg/d (National Center forHealth Statistics, 1999; Food and Nutrition Board. Insti-tute of Medicine, 2001; Cotton et al., 2004), suggesting thatthe doses used in the reviewed trials (5- to 20-fold higherthan what is typically consumed in the diet) are adequate toassess safety of supplementation. The absence of any pat-tern of adverse eVects related to lutein consumption in any

A. S

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TablPubl

Stud NOAEL Considerations

Dag(2 s;

40 mg, but lack of a randomized, double-blind, controlled trial argues against use of this study for the identiWcation of an OSL

Bahr(2 s

30 mg, but lack of relevant clinical measurements (e.g. serum levels) and disease nature of subjects argues against the use of this study for identiWcation of an OSL.

ThuretnD

20.5 mg in healthy adults, acceptable duration of exposure but small sample size; this study could serve as the basis for the human OSL

Alem(2

to al

20 mg, substantial duration of exposure and larger sample size; based on the Wndings from studies above, this study is chosen to serve as the basis of the human OSL

Olm(2

%

15 mg, supports the OSL selected

Gran(1

%


Hini(2

to 15 mg, supports the OSL selected

Hug(2


Olm(2


Zhao(2


Rich(2 ;


RooetnD


e 1ished safety observations for human lutein supplementation

y Study population Dosage and study design Duration (days)

Key observations.

nelie et al. 000) n D 16

Retinitis pigmentosa patients

40 mg/d [followed by 20 mg/d] all-trans lutein, open label conducted via the internet

9 wk (63 d) [17 wk (119 d)]

Serum lutein not analyzed; participants submitted subjective reports of vision changetwo participants reported deterioration in vision

ami et al. 006) n D 34

Retinitis pigmentosa patients

10 mg/d [followed by 30 mg/d] all- trans lutein; randomized, controlled, conducted via the internet

12 wk (84 d) [12 wk (84 d)]

Serum lutein not analyzed; participants submitted subjective reports of vision change

mann al. (2005)

8

Healthy adults 20.5 mg/d all-trans lutein; randomized, controlled

42 d SigniWcant 9-fold increase in serum lutein (to1320 nmol/L); no adverse eVects observed

an et al. 001)n D 29

Healthy adults and patients with retinal degeneration

20 mg/d all-trans lutein; randomized, controlled

6 mo (180 d) SigniWcant 4.6-fold increase in serum lutein (1062.5 nmol/L); half the subjects experiencedsigniWcant increase in macular pigment opticdensity (MPOD); no adverse eVects reported

edilla et al. 002) n D 90

Healthy adults 15 mg/d lutein (12 mg trans, 3 mg cis); randomized, controlled

20 wk (140 d) SigniWcant 5-fold increase in serum lutein (to1250 nmol/L); carotenodermia observed in 40of subjects; no other adverse eVects observed

ado et al. 998) n D 18

Healthy adults 15 mg/d lutein (as mixed lutein esters); randomized, controlled

4 mo (120 d) SigniWcant 5-fold increase in serum lutein (to1370 nmol/L); carotenodermia observed in 40of subjects; no other adverse eVects observed

nger et al. 001) n D 42

Healthy men 15 mg/d lutein (as marigold Xower extract); randomized, controlled

12 wk (84 d) SigniWcant 4.3-fold increase in serum lutein (940 nmol/L); no adverse eVects observed

hes et al. 000) n D 21

Healthy adults 15 mg/d all-trans lutein; randomized, controlled

26 d SigniWcant 4.7-fold increase in serum lutein (1753 nmol/L); no adverse eVects reported

edilla et al. 003)n D 6

Cataract patients 15 mg/d lutein (12 mg trans, 3 mg cis); randomized, controlled

24 mo (730 d) SigniWcant 2-fold increase in serum lutein (to630 nmol/L); no adverse eVects observed

et al. 006) n D 8

Healthy postmenopausal women

12 mg/d all-trans lutein; randomized, controlled

8 wk (57 d) SigniWcant 5.1-fold increase in serum lutein (1500 nmol/L); signiWcant decrease in endogenous DNA damage vs. placebo; no adverse eVects reported

er et al. 004) n D 59

AMD patients 10 mg/d all-trans lutein; randomized, controlled

12 mo (365 d) Serum lutein not analyzed; patients experienced signiWcant 40% increase in MPODno signiWcant diVerence in adverse eVects vs. placebo

denburg al. (2000)

15

Healthy adults 8 mg/d lutein (as lutein esters); randomized, controlled

7 d SigniWcant 2.1-fold increase in serum lutein (365 nmol/L); no adverse eVects reported


of the published human trials provides support for a highlevel of conWdence in the safety of this compound.

There is no concern that excess lutein might contribute tovitamin A (retinol) toxicity, as it is not a substrate for the15,15-monooxygenase enzyme that cleaves �-carotene intovitamin A, and therefore it possesses no pro-vitamin Aactivity. Thus, since lutein does not serve as a source of vita-min A for the body, it is unlikely to exert adverse eVectsanalogous to vitamin A toxicity (Russell, 2000; Fraser andBramley, 2004). Several clinical trials published in the mid-1990s raised concerns regarding a link between �-carotenesupplementation (20–30 mg/day) and lung cancer in life-long smokers (Albanes et al., 1995) or asbestos workers(Omenn et al., 1996). Such concerns do not apply to lutein,as the mode of that eVect of �-carotene appears to be relatedto pro-vitamin A activity (Wang et al., 1999; Russell, 2004).There are reports in the literature of extremely high caroten-oid doses resulting in the precipitation of crystals in the ret-ina of exposed monkeys (Goralczyk et al., 1997; Goralczyket al., 2000). However, these have not involved lutein and arelimited to a carotenoid (canthaxanthin) with chemical andphysical characteristics distinct from those of lutein. Theonly documented side eVect of lutein supplementation iscarotenodermia, a reversible condition characterized by ayellowish discoloration of the skin resulting from elevateddermal carotenoid levels. The condition is most often associ-ated with high �-carotene intake from foods or supplements(>30 mg/d) (Bendich, 1988), and has been reported in onlytwo clinical trials involving lutein, both using daily doses of15 mg for 4–5 months (Granado et al., 1998; Olmedilla et al.,2002). The Institute of Medicine recognizes carotenodermiaas a harmless biological eVect of high carotenoid intake(Food and Nutrition Board. Institute of Medicine, 2000).

3.2. Animal and in vitro studies

Animal and in vitro studies addressing the safety as wellas the metabolism and metabolic eVects of lutein have beenreviewed in detail (Alves-Rodrigues and Shao, 2004). TheLD50 of all-trans lutein has not yet been formally identiWed,but rat studies using doses ranging from 35mg/rat/d (Jenkinset al., 2000) up to 639 mg/kg/d (Kruger et al., 2002) with noassociated toxicity are described in the literature. The resultsof teratogenicity and mutagenicity studies conducted alsoshowed no irreversible adverse eVects at comparable dosages.Assuming a 60kg adult body weight, a 10 mg daily dose inhumans amounts to 170�g/kg, and a 40mg dose equals670�g/kg. These doses appear to be inWnitesimally small incomparison to those used in the animal toxicity studies,which themselves did not cause adverse eVects.

4. Human NOAEL or OSL (HOI)—lutein

4.1. Human NOAEL

None of the clinical trials found an adverse eVect relatedto lutein administration, and therefore there is, by deWni-

tion, no basis for identifying a LOAEL. In the absence of aLOAEL, a NOAEL is not usually set. Without either ofthese two values a UL usually is not set (Food andNutrition Board. Institute of Medicine, 1998b).

4.2. Human OSL

Published relevant human clinical trials involved luteindoses of 8, 10, 12, 15, 20, 20.5, 30 and 40 mg/d (Granadoet al., 1998; Dagnelie et al., 2000; Hughes et al., 2000;Roodenburg et al., 2000; Aleman et al., 2001; Hiningeret al., 2001; Olmedilla et al., 2002, 2003; Richer et al., 2004;Thurmann et al., 2005; Zhao et al., 2006; Bahrami et al.,2006). All human studies reviewed, with the exception ofDagnelie et al. (2000), are double-blind, randomized, con-trolled trials. A series of non-randomized, uncontrolled oropen-label clinical trials has also been published. The dos-ages involved in these studies ranges from 2.4 to 30 mg/d,the results of which are consistent with respect to safety,showing no observed or reported adverse eVects (Berends-chot et al., 2000; Duncan et al., 2002; Bone et al., 2003;Cardinault et al., 2003; Koh et al., 2004).

4.3. 40 mg/d

Although the absence of adverse eVects with 40 mg/d inthe study by Dagnelie et al. (2000) suggests this dose isappropriate for setting the OSL, the lack of a control groupargues against a conWdent use of these data to identify anOSL for healthy adults.

4.4. 30 mg/d

The second highest dose tested in a published, double-blind, placebo-controlled trial is at 30 mg/d (preceded by10 mg/d for 12 weeks) for 12 weeks (Bahrami et al., 2006).While no adverse eVects were reported in this study, thelack of clinically relevant measurements (i.e. serum luteinresponse) and the disease nature of the subjects argueagainst the use of these data to identify and OSL forhealthy adults.

4.5. 20 mg/d

The next highest dose tested in a published, double-blind, placebo-controlled trial is at 20 mg/d for 180 days in29 adults (Aleman et al., 2001). Subjects receiving this levelof lutein experienced a 4.6-fold increase in serum lutein (to1062.5 nmol/L), with no adverse eVects. The completeabsence of adverse eVects in all the published human trialsusing lutein doses above, at, and below the 20 mg levelprovide suYcient support for this value to conWdently bedesignated as the OSL.

Populations exist where the habitual consumption oflutein and other carotenoids is extremely high. In theFiji Islands, for example, the daily consumption ofdark greens exceeds 200 g, providing nearly 25 mg of lutein

A. Shao, J.N. Hathcock / Regulatory Toxicology and Pharmacology 45 (2006) 289–298 293

(Le Marchand et al., 1995). The quantities of luteininvolved in these trials are supplemental amounts wellabove the average amount consumed in foods consumed inthe U.S. (less than 2 mg/d). Therefore, this risk assessmentrepresents a direct approach to an ULS. No correction isneeded for the lutein present in the U.S. food supply.

4.6. Uncertainty evaluation

The highest lutein dose from published animal toxicitystudies is reported by Kruger et al. (2002). A dose of639 mg/kg/d in rats for 4 weeks caused no adverse eVects.This equates to approximately 38,000 mg in a healthy 60 kgadult. While the limited rat data do provide some level ofconWdence in the safety of lutein at the intakes noted, thereare important species-speciWc diVerences that exist betweenrats and humans with respect to the absorption and metab-olism of carotenoids and other lipid-soluble compoundsthat preclude direct extrapolation of the research from onespecies to the other (Castenmiller and West, 1998; West andCastenmiller, 1998; Borel, 2003). Application of a 1000-folduncertainty factor (UF) would result in a ULS of 38 mg.Therefore, no adjustment for uncertainty is required inrelation to the OSL of 20 mg/day based on human data.

NOAEL and LOAEL: >40 mg/d all-trans luteinOSL: 20 mg/d all-trans luteinULS:

• 20 mg/d based on randomized, controlled human trials• 38 mg/d all-trans lutein based on extrapolation from ani-

mal data.

5. ScientiWc evidence related to safety—lycopene

5.1. Human studies

There have been more than thirty peer-reviewed, pub-lished human intervention trials involving various forms oflycopene. Of these, the 16 most relevant studies regardingsafety are presented in this review (Table 2). Criteria forstudy inclusion were study duration (at least 1 week),lycopene dose utilized (greater than 8 mg/d), and studieshad to be randomized, placebo-controlled intervention tri-als. Studies that were uncontrolled and unblinded, thoseinvestigating acute bioavailability, pharmacokinetics orpost-prandial responses from single bolus doses wereexcluded from this analysis, and are used solely as support-ive information. Also excluded were studies that did notquantify the dosage of lycopene being administered (suchas certain feeding studies). Lycopene exists in nature inseveral isomeric forms (Khachik et al., 2002), with themajority of both natural and synthetic sources of supple-mental lycopene being in the trans form (Hoppe et al.,2003). For the purposes of this review, human trial data arelimited to the use of total or trans lycopene, as speciWed.Only a few of the studies undertaken to assess the beneWcial

eVects of lycopene have monitored any possible adverseside eVects, and then primarily through self-reporting.There are no human studies that have focused speciWcallyon the safety of lycopene supplementation. Two compre-hensive reviews have been published examining the safetyof natural (Matulka et al., 2004) and synthetic (McClainand Bausch, 2003) sources of supplemental lycopene. Bothreviews concluded, based on the available human and ani-mal toxicity data, there is no indication of any signiWcantadverse eVects of lycopene.

The highest lycopene dosage utilized in a randomized,controlled human clinical trial was 150 mg/d for 7 days(Rao and Agarwal, 1998). The longest duration trial was 20weeks (140 d) at a lycopene dose of 13.3 mg/d in healthyadults (Olmedilla et al., 2002). Due to diVerences in studyduration and variations in bioavailability from diVerentlycopene sources, serum lycopene levels did not appear tofollow a consistent dose-dependent response. Althoughsupplemental forms of lycopene derived from synthetic andnatural sources appear to have comparable bioavailability(Hoppe et al., 2003), this is not the case with other dietarylycopene sources, such as raw or processed tomatoes ortomato juice (Gartner et al., 1997; Cohn et al., 2004; Tanget al., 2005). Other potential confounders include the incon-sistencies in the amount of time allowed for depletion and/or wash-out phases, which varied considerably betweenstudies and the baseline lycopene status of the subjectsbeing tested. However, irrespective of these inter-studyinconsistencies, there were no adverse eVects observed orreported at any intake in any of the reviewed studies.

Mean level of lycopene consumption from foods byAmericans has been estimated at just over 8 mg/d (Matu-lka et al., 2004), suggesting that the doses used in thereviewed trials (up to many times higher than what istypically consumed in the diet) are adequate to assesssafety of supplementation. The absence of any pattern ofadverse eVects related to lycopene consumption in any ofthe published human trials provides support for a highlevel of conWdence in the safety of this compound.

The only documented side eVect of lycopene supplemen-tation is carotenodermia, a condition characterized by ayellowish discoloration of the skin resulting from elevateddermal levels. The condition is most often associated withhigh �-carotene intake from foods or supplements (>30 mg/d) (Bendich, 1988), has been reported in only a fewinstances involving lycopene (Reigh, 1960; La Placa et al.,2000; Olmedilla et al., 2002), and is recognized as a harm-less reversible nuisance eVect (Food and Nutrition Board.Institute of Medicine, 2000). In contrast to �-carotene,emerging research suggests that lycopene may have aprotective eVect against smoking-induced lung cancer(Liu et al., 2003; Wang, 2005; Liu et al., 2006).

5.2. Animal and in vitro studies

Animal and in vitro studies addressing the safety as wellas the metabolism and metabolic eVects of lycopene have

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Table 2Published safety observations for human lycopene supplementation

Study Study population Dosage and study design Duration (days) Key observations OSL Considerations

1.9 250 mg, but relatively short duration and small sample size argue against use of this study for identiWcation of an OSL

opene (to tments; ucosa cell

sin forms, ted

75 mg in healthy adults, substantial duration of exposure to multiple forms at a high dosage; based on the Wndings of the study above, this study is chosen to serve as the basis for the human OSL

ycopene ported


lycopene eported


in serum bserved


ycopene ported


in serum s, ase in o adverse


lycopene eported


lycopene bserved


lycopene reported


n serum 0 nmol/L, rved


ycopene ported


opene eported


lycopene ported

13.3 mg, supports the OSL selected

ycopene eported

13.3 mg, supports the OSL selected

lycopene e in o; no


Rao and Agarwal (1998) n D 20

Healthy adults 75, 150 mg/d lycopene (as tomato oleoresin); randomized, controlled, crossover

7 d SigniWcant 2, and 2.4-fold increase, respectively, in serum lycopene (to 66and 793.8 nmol/L) vs. placebo; no adverse eVects reported

Paetau et al. (1998, 1999) n D 15

Healthy adults 70 mg/d lycopene (as beadlets), 75 mg/d (as oleoresin and tomato juice, respectively) ; randomized, controlled, crossover

4 wk (28 d) SigniWcant 41% increase in serum lycapprox. 825 nmol/L) for all three treasigniWcant 2-fold increase in buccal mlycopene level for beadlet and oleorerespectively; no adverse eVects repor

Watzl et al. (2000) n D 29

Healthy elderly 47 mg/d lycopene (as tomato juice); randomized, controlled

8 wk (56 d) SigniWcant 4-fold increase in serum l(to 540 nmol/L); no adverse eVects re

Maruyama et al. (2001) n D 10

Healthy female adults 45 mg/d lycopene as tomato juice; randomized, controlled

29 d SigniWcant 2.8-fold increase in serum(to 1842 nmol/L); no adverse eVects r

Kucuk et al. (2001, 2002) n D 15

Prostate cancer patients

30 mg/d lycopene (as tomato oleoresin); randomized, controlled

3 wk (21 d) No signiWcant changes for lycopene or tumor tissues; no adverse eVects o

Neuman et al. (2000) n D 20

Exercise-induced asthma patients

30 mg/d lycopene (as tomato oleoresin); randomized, controlled, crossover


Richelle et al. (2002) n D 22

Healthy adults 25 mg/d lycopene (as tomato paste or oleoresin, respectively); randomized, controlled

8 wk (56 d) SigniWcant 2.7 and 2.5-fold increaseslycopene in the two treatment grouprespectively; signiWcant 3.7-fold incremuccal mucosa cell lycopene level; neVects reported

Horvitz et al. (2004) n D 9

Healthy adults 20 mg/d lycopene (as tomato paste); randomized, controlled, crossover

11 d SigniWcant 2.4-fold increase in serum(to 3430 nmol/L); no adverse eVects r

Briviba et al. (2004) n D 27

Healthy smoking and nonsmoking adults

15 mg/d lycopene (as tomato paste); randomized, controlled, crossover

2 wk (14 d) SigniWcant 3.3-fold increase in serum(to 800 nmol/L); no adverse eVects o

Hininger et al. (2001) n D 52

Healthy men 15 mg/d lycopene (as tomato oleoresin); randomized, controlled

12 wk (84 d) SigniWcant 1.9-fold increase in serum(to 1170 nmol/L); no adverse eVects

Hoppe et al. (2003) n D 24

Healthy adults 15 mg/d lycopene (as tomato oleoresin or synthetic lycopene, respectively); randomized, controlled

28 d SigniWcant 2.5 and 2.8-fold increase ilycopene, respectively (to 950 and 91respectively); no adverse eVects obse

Astley et al. (2004) n D 28

Healthy men 15 mg/d lycopene (as tomato oleoresin); randomized, controlled, crossover


Hughes et al. (2000) n D 23

Healthy adults 15 mg/d lycopene (as tomato oleoresin); randomized, controlled

26 d SigniWcant 44% increase in serum lyc(to 1010 nmol/L); no adverse eVects r

Corridan et al. (2001) n D 17

Health elderly 13.3 mg/d lycopene (as tomato oleoresin); randomized, controlled

12 wk (84 d) SigniWcant 2.7-fold increase in serum(to 270 nmol/L); no adverse eVects re

Olmedilla et al. (2002) n D 93

Healthy adults 13.3 mg/d lycopene (as tomato oleoresin); randomized, controlled

20 wk (140 d) SigniWcant 2-fold increase in serum l(to 1200 nmol/L); no adverse eVects r

Zhao et al., 2006 n D 8

Healthy postmenopausal women

12 mg/d lycopene (as synthetic lycopene); randomized, controlled

8 wk (57 d) SigniWcant 2.6-fold increase in serum(to 1300 nmol/L); signiWcant decreasendogenous DNA damage vs. placebadverse eVects reported


been reviewed in detail (McClain and Bausch, 2003; Matu-lka et al., 2004). For natural lycopene (derived from tomatooleoresin), the LD50 in rats was not established but wasdetermined to be more than 5000 mg/kg body weight, andthe NOAEL established to be more than 4500 mg/kg bodyweight (based on a 13 week study) (Matulka et al., 2004).For synthetic lycopene, no adverse eVects were detected upto the highest dose of 1000 mg/kg body weight for 4 weeksor 500 mg/kg body weight for 13 weeks (McClain andBausch, 2003). The results of teratogenicity and mutagenic-ity studies conducted on both lycopene forms also showedno irreversible adverse eVects at comparable dosages. Sucha large margin of safety from animal studies provides ahigh level of conWdence that supplemental lycopene,regardless of the form, can be consumed safely at relativelyhigh doses by humans.

6. Human NOAEL or OSL (HOI)—lycopene

6.1. Human NOAEL

As with lutein, none of the clinical trials found anadverse eVect related to lycopene administration, and there-fore there is, by deWnition, no basis for identifying aLOAEL. In the absence of a LOAEL, a NOAEL is not usu-ally set. Without either of these two values a UL usually isnot identiWed (Food and Nutrition Board. Institute ofMedicine, 1998b).

6.2. Human OSL

Published relevant human clinical trials involved lyco-pene doses of up to 150 mg/d (Rao and Agarwal, 1998). Allhuman studies reviewed were double-blind, randomized,controlled trials. A series of non-randomized, open-labelclinical trials has also been published. The dosages involvedin these studies ranges from 20 to 37 mg/d, the results ofwhich are consistent with respect to safety, showing noobserved or reported adverse eVects (Chen et al., 2001;Watzl et al., 2003; Cohn et al., 2004; van Breemen, 2005).

6.3. 150 mg/d

Although the absence of adverse eVects with 150 mg/d inthe study by Rao and Agarwal (1998) suggests this dose isappropriate for setting the OSL, the relatively short dura-tion (1 week) and small sample size (nD 20) used argueagainst use of this study for identiWcation of an OSL forhealthy adults.

6.4. 75 mg/d

The next highest dose tested in a published, double-blind, placebo-controlled trial is at 75 mg/d for 4 weeks (28days) in 15 healthy adults (Paetau et al., 1998, 1999). Sub-jects receiving lycopene experienced a signiWcant 41%increase in serum lycopene and signiWcant 2-fold increase in

buccal mucosa cell lycopene level, with no adverse eVectsreported. The longer duration, and the combined result ofno adverse eVects from this study and that of Rao andAgarwal (1998) which also implemented a 75 mg/d dose,provides suYcient support for the designation of this studyas the basis for the human OSL of 75 mg/d.

The remainder of the reviewed trials in Table 2 includelycopene doses ranging from 47 down to 12 mg/d fordurations ranging from 1 to 20 weeks (Hughes et al., 2000;Neuman et al., 2000; Watzl et al., 2000; Corridan et al.,2001; Hininger et al., 2001; Kucuk et al., 2001; Maruyamaet al., 2001; Kucuk et al., 2002; Olmedilla et al., 2002;Richelle et al., 2002; Hoppe et al., 2003; Astley et al., 2004;Briviba et al., 2004; Horvitz et al., 2004; Zhao et al., 2006).The complete absence of adverse eVects in all the publishedhuman trials using lycopene doses above, at, and below the75 mg level provide suYcient support for this value to con-Wdently be designated as the OSL.

The quantities of lycopene involved in these trials aresupplemental amounts well above the estimated averageamount consumed in foods consumed in the U.S. (8 mg/d(Matulka et al., 2004)). Therefore, this risk assessmentrepresents a direct approach to an ULS. No correction isneeded for the lycopene present in the U.S. food supply.

6.5. Uncertainty evaluation

The highest lycopene dose from published animal toxic-ity studies is reported by Matulka et al. using lycopenederived from tomato oleoresin (Matulka et al., 2004). Anacute dose of 5000 mg/kg in rats failed to produce any clini-cal signs of toxicity or death and a sub-chronic dose of upto 4500 mg/kg body weight per day for 13 weeks alsocaused no adverse eVects. This NOAEL in rats equates toapproximately 270 g/d in a healthy 60 kg adult. As wasnoted in the section on lutein, there are important species-speciWc diVerences that exist between rats and humans withrespect to the absorption and metabolism of carotenoidsthat preclude direct extrapolation of the research from onespecies to the other (Castenmiller and West, 1998; West andCastenmiller, 1998; Borel, 2003). Application of a 1000-folduncertainty factor (UF) would result in a ULS of 270 mg.

NOAEL and LOAEL: >150 mg/d lycopeneOSL: 75 mg/d lycopeneULS:

• 75 mg/d based on randomized, controlled human trials• 270 mg lycopene based on extrapolation from animal

data.

7. Conclusions

In summary, lutein and lycopene are two of the mostprevalent carotenoids in the human diet and serum. Thecontinuously emerging research on the health beneWts ofthese compounds, combined with their increased use indietary supplement products, warranted the present risk


assessment evaluation. The absence of any clear adverseeVects from the available published human clinical andanimal data on lutein and lycopene provide a high level ofconWdence in both of these ingredients with respect to theirsafe use in dietary supplements. The absence of a well-deWned critical eVect for either ingredient precludes theselection of a NOAEL, and therefore required use of theobserved safe level (OSL) or highest observed intake (HOI)approach established by FAO/WHO to conduct this riskassessment. Evidence from well-designed randomized, con-trolled human clinical trials indicates that the Upper Levelfor Supplements (ULS) for all-trans lutein is 20 mg per day(38 mg all-trans lutein based on extrapolation from animaldata). For lycopene, the same approach yields a substan-tially higher ULS of 75 mg per day (270 mg based onextrapolation from animal data).

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