National Toxicology Program 

NTP
 

CURRENT DIRECTIONS and EVOLVING STRATEGIES
 
  

Table of Contents
 	 4	 Overview	of	the	National	Toxicology	Program 

	10	 Current	Directions 

16	 Evolving	Strategies 

22	 Centers 

26	 Report	on	Carcinogens 

	28	 Outreach	 

2 National Toxicology Program 
  

	 ATSDR	 Agency	for	Toxic	Substances	and	Disease	Registry 

	 BSC	 Board	of	Scientific	Counselors 

		 CDC	 Centers	for	Disease	Control	and	Prevention	 

	 CDM	 Central	Data	Management 

	 CERHR	 Center	for	the	Evaluation	of	Risks	to	Human	Reproduction 

	 CPSC	 Consumer	Product	Safety	Commission 

	 DHHS	 Department	of	Health	and	Human	Services 

	 EPA	 Environmental	Protection	Agency 

	 FDA	 Food	and	Drug	Administration 

	 HTS	 High	Throughput	Screening 

	 ICCEC	 Interagency	Committee	for	Chemical	Evaluation	and	Coordination 

	 ICCVAM	 Interagency	Coordinating	Committee	on	the	Validation	of	Alternative	Methods 

	 MLI	 Molecular	Libraries	Initiative 

	 MRI	 Magnetic	Resonance	Imaging 

	 NCEH	 National	Center	for	Environmental	Health 

	 NCI	 National	Cancer	Institute 

	 NCP	 NTP	Center	for	Phototoxicology 

	 NCTR	 National	Center	for	Toxicological	Research 

NICEATM	 NTP	Interagency	Center	for	the	Evaluation	of	Alternative	Toxicological	Methods 

	 NIEHS	 National	Institute	of	Environmental	Health	Sciences 

	 NIH	 National	Institutes	of	Health 

	 NIOSH	 National	Institute	for	Occupational	Safety	and	Health 

	 NTP	 National	Toxicology	Program 

	 OSHA	 Occupational	Safety	and	Health	Administration 

	 PBPK	 Physiologically	Based	Pharmacokinetic 

	 PCB	 Polychlorinated	Biphenyl 

	 RoC	 Report	on	Carcinogens 

	 SACATM	 Scientific	Advisory	Committee	on	Alternative	Toxicological	Methods 

	 TCDD	 2,3,7,8-Tetrachlorodibenzo-p-dioxin 

	 TEF	 Toxic	Equivalency	Factor 

	 UV	 Ultraviolet 

	 WHO	 World	Health	Organization 

National Toxicology Program 3 
  

Overview 

Mission and Goals 

More	than	80,000	chemicals	are	registered	for	use	in	the	United	States.	Each	year,	an	estimated	 

2,000	new	substances	are	introduced	for	use	in	such	everyday	items	as	foods,	personal	care	products,	 

prescription	drugs,	household	cleaners,	and	lawn	care	products.	An	estimated	500	to	600	new	industrial	 

chemicals	are	introduced	annually	to	the	U.S.	commerce.	We	do	not	know	the	effects	of	many	of	these	 

substances	on	our	health,	yet	we	may	be	exposed	to	them	while	manufacturing,	distributing,	using,	 

and	disposing	of	them	or	when	they	become	pollutants	in	our	air,	water,	or	soil.	While	relatively	few	 

chemicals	are	thought	to	pose	a	significant	risk	to	human	health,	safeguarding	public	health	depends		 

on	identifying	both	what	the	effects	of	these	substances	are	and	at	what	levels	of	exposure	they	may	 

become	hazardous	to	humans—that	is,	understanding	their	toxicology.	 

The	National	Toxicology	Program	(NTP)	was	established	in	1978	to	(1)	coordinate	toxicology		 

testing	programs	within	the	federal	government,	(2)	strengthen	the	science	base	in	toxicology,		 

(3)	develop	and	validate	improved	testing	methods,	and	(4)	provide	information	about	potentially		 

toxic	chemicals	to	health,	regulatory,	and	research	agencies,	scientific	and	medical	communities,		 

and	the	public.	The	NTP	is	an	interagency	program	within	the	U.S.	Department	of	Health	and		 

Human	Services	(DHHS)	whose	mission	is	to	evaluate	environmental	substances	of	public	health	 

concern	by	developing	and	applying	tools	of	modern	toxicology	and	molecular	biology.	The	program	 

maintains	an	objective,	science-based	approach	in	dealing	with	critical	issues	in	toxicology	and	is	 

committed	to	using	the	best	science	available	to	prioritize,	design,	conduct,	and	interpret	its	studies.		 

To	that	end,	the	NTP	is	continually	evolving	to	remain	at	the	cutting	edge	of	scientific	research,	 

and	to	develop	and	apply	new	technologies.	 

Current Activities 

The	NTP	maintains	a	number	of	complex,	interrelated	research	and	testing	programs	that	provide	 

unique	and	critical	information	needed	by	health,	regulatory,	and	research	agencies	to	evaluate		 

potential	human	health	effects	from	chemical	and	physical	exposures.	All	of	the	NTP’s	activities	are	 

open	to	public	scrutiny	including	communications	with	all	interested	parties.	The	NTP	has	always	 

drawn	strength	and	direction	from	the	commitment	of	its	scientists	to	exchange	information	openly,	 

maintain	impartiality,	and	apply	rigorous,	scientific	peer	review.	This	is	a	central	priority	of	the		 

program	now	and	will	remain	so	in	the	future.	 

The	NTP	seeks	to	maintain	a	balanced	research	and	testing	program	that	provides	data	on	a	wide	 

variety	of	issues	important	to	public	health.	In	particular,	the	NTP	seeks	nominations	of	studies	that	 

4 National Toxicology Program 
  

(1)	fill	significant	gaps	in	the	knowledge	of	the	toxicity	of	chemicals	or	classes	of	chemicals,	(2)	address	 

mechanisms	of	toxicity,	or	(3)	enhance	the	predictive	ability	of	future	NTP	studies.	Currently,	the	 

NTP	is	focusing	on	several	areas	that	have	received	inadequate	attention	in	the	past.	Some	examples	 

include	photoactive	chemicals,	contaminants	of	finished	drinking	water,	endocrine-disrupting	agents,	 

and	certain	complex	occupational	exposures.	The	NTP	is	addressing	potential	safety	issues	associated	 

with	herbal	medicines,	radiofrequency	radiation	emissions	from	cellular	telephones,	perfluorinated	 

compounds,	and	nanoscale	materials.	In	general,	these	initiatives	are	broad-based	and	investigate		 

various	health-related	effects.	 

The	NTP	continues	to	work	to	develop	and	validate	alternative	testing	methods	that	will	help		 

identify	environmental	hazards	using	fewer	test	animals.	This	effort	includes	developing	more		 

efficient,	mechanism-based	testing	strategies	that	provide	information	about	how	a	substance		 

affects	biological	processes,	such	as	genetically	engineered	models	for	toxicology	testing,	and	 

implementing	gene	expression	technologies.	The	NTP	is	currently	studying	how	to	use	in vitro		 

high	throughput	assays	for	screening	large	numbers	of	substances	for	specific	biological	or	toxic		 

effects	and	for	setting	priorities	for	further	toxicological	evaluations.	These	methods	hold	the		 

promise	of	providing	a	true	mechanistic	basis	for	identifying	and	studying	environmental	toxicants.	 

The	NTP	also	evaluates	whether	human	exposures	to	environmental	agents	cause	adverse	effects		 

on	reproduction,	development,	and	the	immune,	respiratory,	and	central	nervous	systems.	The		 

NTP	is	expanding	its	effort	to	include	routine	investigations	of	changes	in	the	immune	system		 

and	the	nervous	system	from	exposures	occurring	during	fetal	development	and	early	life.	 

The	NTP	continues	to	expand	activities	designed	to	place	research	and	testing	results	from	animals	 

in	a	perspective	that	is	more	relevant	to	human	health.	This	includes	human	exposure	assessment,	 

toxicokinetics,	mechanism-based	pharmacokinetic	modeling,	and	interpreting	results	in	molecular	 

epidemiology	for	use	in	identifying	human	hazards	(e.g.,	the	Report	on	Carcinogens	and	the	NTP’s	 

Center	for	the	Evaluation	of	Risks	to	Human	Reproduction).	The	NTP	is	also	coordinating	an	effort	 

to	obtain	“real-world”	information	about	worker	practices,	complex	occupational	exposures,	and	 

potentially	related	adverse	health	effects.	We	need	such	information	to	identify	areas	for	research	and	 

to	design	better	laboratory	studies	on	the	potential	health	effects	of	chemicals,	complex	mixtures,	and	 

exposures	people	encounter	in	the	workplace. 

National Toxicology Program 5 
  

Overview 

NTP Roadmap for the 21st Century 

For	more	than	25	years,	the	NTP	has	been	a	leader	in	toxicology	testing	and	research	within	the	 

United	States	and	has	contributed	significantly	to	the	scientific	knowledge	upon	which	public	health	 

decisions	are	based.	While	the	NTP	has	studied	more	than	2,500	substances,	including	more	than	500	 

for	cancer,	relatively	few	of	the	existing	and	new	substances	can	be	evaluated	fully	for	their	potential	 

to	cause	toxicity	because	the	traditional	methods	used,	while	of	great	value	for	predicting	biological	 

responses,	are	time-consuming	and	labor	intensive.	Thus	in	August	2003,	the	NTP	began	reviewing		 

its	current	activities	to	determine	how	to	take	advantage	of	new	scientific	technologies	in	its	research	 

and	testing	strategies,	and	broaden	scientific	knowledge	on	the	link	between	mechanism	and	disease.		 

The	NTP	created	a	vision	for	the	program’s	future	and	in	January	2005	released	its	roadmap	to	address	 

the	goals	of	that	vision	(available	at	http://ntp.niehs.nih.gov	and	select	“NTP	Vision	&	Roadmap”).	 

The	NTP’s	vision	for	the	21st	century	is	to	support	the	evolution	of	toxicology	from	an	observational	 

science	based	on	disease-specific	models	to	a	predominantly	predictive	science	focused	on	a	broad	 

inclusion	of	target-specific,	mechanism-based,	biological	observations.	The	NTP	Roadmap,	developed	 

with	input	from	industry,	academia,	government,	and	advocacy	groups,	identifies	current	challenges	 

and	opportunities,	and	discusses	future	directions	in	three	areas:	(1)	refinement	of	traditional	toxicology	 

assays,	(2)	development	of	rapid,	mechanism-based,	predictive	screens	for	environmentally	induced	 

diseases,	and	(3)	improvement	in	the	overall	utility	of	NTP	products	for	public	health	decisions. 

The	NTP	has	now	begun	to	implement	the	NTP	Roadmap	with	workshops	to	address	current	 

toxicology	and	carcinogenicity	testing	strategies,	a	new	high	throughput	screening	initiative,	and		 

a	focus	on	understanding	host	susceptibility.	If	initiated	successfully,	the	NTP	Roadmap	should		 

enable	the	NTP	to	broaden	its	testing	activities	to	include	more	exposure	scenarios,	address	 

susceptibility	issues	related	to	variability	in	human	genetics,	and	provide	better	and	more		 

targeted	scientific	guidance	for	making	public	health	decisions	aimed	at	preventing	or	reducing		 

adverse	health	effects.	 

Partnerships 

Strengthening	existing	partnerships	and	forging	new	ones	are	important	for	the	NTP	to	achieve		 

its	goals.	The	NTP	has	a	critical	role	to	provide	scientific	data,	interpretations,	and	guidance		 

on	the	appropriate	uses	of	those	data,	and	federal	and	state	government	agencies	rely	on	the		 

scientific	knowledge	base	provided	by	the	NTP	to	make	credible	decisions	that	protect	public		 

health.	The	NTP	also	works	to	(1)	foster	interagency	collaborations	in	research	and	exposure	 

assessment,	(2)	provide	information	to	regulatory	agencies	about	alternative	methods	for	toxicity	 

screening,	and	(3)	explore	new	technologies	for	evaluating	how	environmental	agents	cause	disease.	 

The	NTP	continues	to	develop	international	partnerships	to	establish	efficient	means	to	avoid	 

duplicating	effort(s)	in	toxicology	testing.	The	NTP	is	collaborating	with	the	European	Ramazzini	 

Foundation	of	Oncology	and	Environmental	Sciences	to	create	similar	protocols,	quality	assurance,	 

and	reporting	for	laboratory	studies	on	the	health	effects	associated	with	long-term	exposure	to	 

environmental	agents.	The	NTP	has	a	similar	agreement	with	the	Korea	National	Toxicology	Program.	 

The	NTP	is	also	participating	in	the	World	Health	Organization’s	International	Electric	and	Magnetic	 

Fields	Project	to	facilitate	internationally	coordinated	research	on	the	health	effects	of	electric	and	 

magnetic	fields,	including	those	generated	by	cellular	telephone	technologies.	 

6 National Toxicology Program 
  

 

 

Overview 

Organizational Structure and Oversight 

Three	agencies	form	the	core	of	the	NTP:	(1)	the	National	Center	for	Toxicological	Research	(NCTR)	 

of	the	Food	and	Drug	Administration	(Figure	1),	(2)	the	National	Institute	of	Environmental	Health	 

Sciences	(NIEHS)	of	the	National	Institutes	of	Health,	and	(3)	the	National	Institute	for	Occupational	 

Safety	and	Health	(NIOSH)	of	the	Centers	for	Disease	Control	and	Prevention.	Each	agency	 

voluntarily	provides	resources	to	support	NTP	research,	testing,	centers,	and	outreach.	 

The	NTP	Executive	Committee	(Figure	1)	provides	oversight	to	the	NTP	for	policy	issues.	This	 

committee	is	composed	of	the	heads	(or	their	designees)	of	federal	research	and	regulatory	agencies.	 

The	NTP	Board	of	Scientific	Counselors	(BSC)	and	the	Scientific	Advisory	Committee	on	Alternative	 

Toxicological	Methods	(SACATM)	assure	regular	scientific	and	public	peer	review	and	input	about	 

NTP	activities	and	priorities.	 

The	BSC	is	a	federally	chartered	advisory	committee	whose	members	are	appointed	by	the		 

secretary,	DHHS.	The	BSC	provides	primary	scientific	oversight	to	the	NTP	director	and		 

evaluates	the	scientific	merit	of	the	NTP’s	intramural	and	collaborative	programs.	The	Technical	 

Reports	Review	Subcommittee	of	the	BSC	provides	peer	review	for	the	NTP	(1)	long-term	toxicology		 

and	carcinogenicity	studies,	(2)	studies	conducted	in	genetically	modified	models,	and	(3)	as	needed,	 

short-term	toxicity	reports.	These	groups	meet	once	or	twice	each	year,	and	meetings	are	open		 

to	the	public.	In	addition,	the	BSC,	on	occasion,	convenes	work	groups	to	obtain	an	in-depth	review	of		 

a	specific	topic.	 

The	SACATM	provides	advice	to	the	NIEHS	director,	the	Interagency	Coordinating	Committee	on		 

the	Validation	of	Alternative	Methods,	and	the	NTP	Interagency	Center	for	the	Evaluation	of	 

Alternative	Toxicological	Methods.	This	advice	addresses	priorities	and	directives	related	to	the	 

development,	validation,	scientific	review,	and	regulatory	acceptance	of	new	or	revised	toxicological		 

test	methods,	and	ways	to	foster	partnerships	and	communication	with	interested	parties.	The		 

NIEHS	director	appoints	members	to	this	federally	chartered	advisory	committee.	The	SACATM		 

meets	once	or	twice	each	year,	and	meetings	are	open	to	the	public.	 

The	NTP	also	uses	special	emphasis	panels,	as	needed,	to	provide	independent	scientific	peer	review		 

and	advice	to	the	NTP.	These	panels	help	ensure	transparent,	unbiased,	and	scientifically	rigorous		 

input	to	the	program	for	its	use	in	making	credible	decisions	about	human	health	hazards,	setting	 

research	and	testing	priorities,	and	evaluating	test	methods	for	toxicity	screening.	 

Figure 1 National Toxicology Program 

NCTR 

Director 

NIEHS 

NIOSH 

Policy Oversight 

NTP Executive Committee 

• ATSDR 

• CPSC 

• EPA 

• FDA 

• NCEH 

• NCI 

• NIEHS 

• NIOSH 

• OSHA 

External Science Oversight 

and Peer Review 

NTP Board of Scientific Counselors 

• Technical Reports Review 

Subcommittee 

• Nanotechnology Working Group 

Scientific Advisory Committee on 

Alternative Toxicological Methods 

National Toxicology Program 7 
  

                        

     

                     

                        

                     

                            

                       

                        

                   

                      

                  

   

                    

Overview 

Toxicology and Carcinogenicity Evaluations 

The	NTP	has	a	broad	mandate	to	characterize	chemicals	and	other	agents	of	public	health	concern.	 

The	NTP	continually	solicits	and	reviews	nominations	for	toxicology	studies	for	the	specific	categories	 

listed	in	Table	1.	The	nomination	process	is	open	to	all	interested	individuals	and	groups.	Information	 

about	nominating	a	substance	for	testing	by	the	NTP	is	available	on	the	NTP	website	(http://ntp.niehs. 

nih.gov)	or	by	contacting	Dr.	Scott	Masten,	Office	of	Chemical	Nomination	and	Selection	(for	contact	 

information,	see	inside	back	cover).	 

Table 1 Nomination Principles for NTP Studies 

• Substances found in home, workplace, or ambient environments that are not associated 

with a single commercial organization. 

• Naturally occurring substances that may not be adequately evaluated without federal 

involvement. 

• Commercial products with significant exposure that were first marketed prior to current 

testing requirements or those that generate too little revenue to support further evaluations. 

• Potential substitutes for existing chemicals or drugs that might not be developed without 

federal involvement. 

• Mixtures of substances for which evaluations are not required of industry. 

• Substances that will aid our understanding of chemical toxicities, or our understanding 

of the use of test systems to evaluate potential toxicities. 

• Substances that should be evaluated to improve the scientific understanding of 

structure-activity relationships and thereby help limit the number of substances 

requiring extensive evaluations. 

• Emergencies or other events that warrant immediate federal government evaluation of 

a substance. 

Nominations	undergo	several	levels	of	review	before	the	NTP	selects	agents	for	study	(Figure	2).	 

Representatives	from	federal	agencies	on	the	Interagency	Committee	for	Chemical	Evaluation	and	 

Coordination	(ICCEC)	and	the	BSC	participate	in	the	selection	process.	The	NTP	also	solicits	and	 

considers	public	comment	on	nominations	throughout	this	formal	process.	As	the	final	step,	the	NTP	 

Executive	Committee	reviews	and	evaluates	the	testing	recommendations	and	the	public	comments		 

for	each	nomination.	The	committee	makes	its	own	recommendations	on	the	nominations:	(1)	to	test,	 

(2)	not	to	test	at	this	time,	or	(3)	to	defer	testing	until	more	information	is	received	and	considered.	 

These	steps	help	ensure	that	the	NTP’s	testing	program	addresses	toxicological	concerns	pertinent		 

to	all	areas	of	public	health	and	maintains	balance	among	the	types	of	substances	evaluated.	 

The	Executive	Committee’s	recommendation	of	a	substance	for	study	does	not	automatically	 

commit	the	NTP	to	its	evaluation.	The	NTP	strives	to	balance	its	selection	of	substances	for	study	 

(e.g.,	occupational	exposures,	environmental	pollutants,	food	additives,	consumer	products,	and	 

pharmaceuticals)	and	launches	studies	as	time	and	resources	permit.	In	reviewing	and	selecting	 

nominated	substances	for	study,	the	NTP	also	considers	legislative	mandates	that	require	responsible	 

private	sector	and	commercial	organizations	to	evaluate	their	products	for	human	and	environmental	 

health	effects.	Also,	a	nomination	selected	for	study	may	be	deferred	at	any	time	if	suitable	data	become	 

available,	if	higher	priority	studies	are	identified,	or	if	a	study	proves	impractical.	 

8 National Toxicology Program 
  

 

 

 

Overview 

The	NTP	evaluates	substances	for	a	variety	of	health-related	effects,	among	them,	general	toxicity,	 

reproductive	and	developmental	toxicity,	genotoxicity,	immunotoxicity,	neurotoxicity,	and	 

carcinogenicity.	The	NTP	generally	uses	rodent	models	for	study	and	conducts	short-term	studies	for	 

up	to	thirteen	weeks	and	long-term	studies	for	up	to	two	years.	For	each	agent	studied,	a	project	leader	 

designs	a	comprehensive	testing	strategy	to	address	the	identified	research	and	testing	needs.	A	project	 

review	committee	evaluates	the	testing	strategy	and	proposes	an	appropriate	mechanism	for	sponsoring	 

the	study	(e.g.,	grant,	contract,	etc.).	 

The	NTP	publishes	results	of	short-term	rodent	toxicology	studies	in	the	NTP	Toxicity	Report	series	 

and	results	of	long-term	studies,	generally	two-year	rodent	toxicology	and	carcinogenicity	studies,	as	 

NTP	Technical	Reports	or	in	peer-reviewed	scientific	journals.	During	2003,	the	NTP	began	a	new	 

technical	report	series	for	reporting	the	results	from	studies	conducted	in	genetically	modified	models	 

such	as	genetically	engineered	mice.	Completed	reports	are	available	electronically	from	the	NTP	 

website	(http://ntp.niehs.nih.gov	and	select	“Publications,	Technical	Reports,	and	Abstracts”)	or	in	hard	 

copy	from	Central	Data	Management	(for	contact	information,	see	inside	back	cover).	 

Figure 2 NTP Toxicology Study Nomination and Selection Process 

Federal and State Agencies 

Labor Public International Organizations 

Chemical 

Nominations 

ICCEC Review 

Public Review 

NTP Board of Scientific Counselors Review (Public Meeting) 

NTP Executive Committee Review and Selection 

NTP Designs and Initiates Studies Based on Resources, Priorities, and Knowledge Gaps 

Industry 

Industry Academia Other Organizations 

National Toxicology Program 9 
  

Current Directions
 

The	NTP	conducts	research	on	a	broad	range	of	high-priority	agents	and	issues	of	public	health	 

concern.	Information	about	NTP	studies,	including	standard	protocols,	fact	sheets,	and	data	from	 

completed	studies,	is	available	on	the	NTP	website	(http://ntp.niehs.nih.gov).	Below	are	brief		 

overviews	of	some	current	initiatives.	 

Radiofrequency Radiation Emissions from Cellular Phones 

More	than	200	million	Americans	currently	use	wireless	communication	devices,	with	thousands		 

of	new	users	added	daily.	Personal	(cellular)	telecommunications	is	a	rapidly	evolving	technology		 

that	uses	microwave	radiation	to	communicate	between	a	fixed	base	station	and	a	mobile	user.	Most		 

systems	employ	a	handheld	cellular	telephone,	with	the	radiation	antenna	held	close	to	the	user’s	head.	 

The	Federal	Communication	Commission	requires	cellular	phones	and	other	wireless	communication	 

devices	to	meet	its	guidelines	for	exposure	to	radiofrequency	radiation.	These	guidelines	are	based	 

on	protecting	the	user	from	immediate	injury	from	the	heat	produced	by	radiofrequency	radiation.	 

However,	we	currently	do	not	have	enough	data	to	determine	whether	these	guidelines	will	also		 

protect	against	potential	adverse	effects	of	long-term	exposure.	 

Studies	in	laboratory	animals	are	crucial	for	understanding	whether	long-term	exposure	to	 

radiofrequency	radiation	may	pose	a	danger	to	human	health.	The	NTP	is	studying	the	toxic		 

and	carcinogenic	effects	of	chronic	exposure	to	cellular	phone	radiofrequency	radiation	emissions		 

in	laboratory	animals.	The	NTP	worked	with	technical	experts	from	the	National	Institute		 

of	Standards	and	Technology	to	demonstrate	the	suitability	of	using	reverberation	chambers		 

to	expose	animals	to	uniform	fields	of	cellular	phone	radiofrequency	radiation.	These	studies	will		 

test	radiofrequency	signals	that	simulate	exposures	of	cellular	phone	users	to	help	clarify	any	potential		 

health	hazard	for	the	U.S.	population.		 

Children’s Health 

The	NTP	continues	to	be	a	leader	in	issues	related	to	children’s	health	through	research	and	the	NTP’s	 

Center	for	the	Evaluation	of	Risks	to	Human	Reproduction.	The	NTP	has	ongoing	efforts	to	evaluate	 

effects	of	various	agents	on	the	developing	immune	and	nervous	systems	through	laboratory	studies		 

of	pesticides,	water	disinfectant	by-products,	and	endocrine-disrupting	agents.	The	program	has		 

expanded	these	efforts	by	establishing	study	protocols	where	perinatal	animals	will	be	given	these		 

10 National Toxicology Program 
  

agents	and	then	examined	for	toxic	effects,	including	developmental	immunotoxicity,	neurotoxicity,		 

and	reproductive	effects.	Toxicokinetic	data	from	animal	studies	of	mothers,	fetuses,	and	newborns		 

will	be	used	to	develop	pharmacokinetic	models	based	on	physiology.	These	models	will	help		 

evaluate	risks	to	humans	from	exposure	to	environmental	toxicants	during	early	development.	 

Phototoxicology 

The	U.S.	public	is	increasingly	exposed	to	ultraviolet	(UV)	radiation	or	sunlight	through	more	frequent	 

use	of	tanning	booths	and	more	leisure	time	spent	in	outdoor	activities.	The	NTP	is	coordinating		 

an	effort	between	the	NIEHS	and	the	NCTR	to	study	how	sunlight	or	UV	radiation	affects	the		 

toxicity	(phototoxicology)	and	carcinogenicity	(photocarcinogenicity)	of	substances	nominated	to		 

the	NTP,	including	those	of	high	priority	to	the	Food	and	Drug	Administration	(FDA).	These	studies	 

use	the	SKH-1	hairless	mouse	as	the	primary	model,	and	new	models	are	also	under	investigation.		 

The	NTP	Center	for	Phototoxicology	also	conducts	studies	to	learn	how	these	toxic	and	carcinogenic	 

effects	might	occur.	 

The	NTP	Center	for	Phototoxicology	is	studying	the	possible	acute	toxicity	and	carcinogenicity	 

of	topically	applied	plant	extracts	of	the	aloe	vera	plant	or	topically	applied	retinyl	palmitate	in	 

combination	with	simulated	sunlight.	Many	products,	including	cosmetics	and	dietary	supplements,	 

contain	portions	of	the	aloe	vera	plant.	Retinyl	palmitate	is	included	in	some	cosmetics	as	an	“antiwrinkle”	compound,	and	its	safety	in	the	presence	of	sunlight	needs	further	study.	Also,	the	NTP	 

Center	for	Phototoxicology	is	designing	and	conducting	studies	of	other	cosmetic	ingredients,	including	 

topically	applied	Padamate	O	used	in	cosmetic	and	sunscreen	preparations,	furocoumarin	compounds	 

found	in	lemon	and	lime	oils,	nanoscale	particles	used	in	sunscreens	(zinc	oxide	and	titanium	dioxide),	 

and	permanent	makeup	inks.	 

Herbal Medicines 

Herbs	are	among	our	oldest	medicines,	and	their	increasing	use	in	recent	years	is	evidence	of	public	 

interest	in	alternatives	to	conventional	medicine.	The	use	of	herbal	medicines	and	other	dietary	 

supplements	has	increased	substantially	since	passage	of	the	1994	Dietary	Supplement	Health	and	 

Education	Act.	Herbal	medicines	are	a	major	market	in	U.S.	pharmacies	and	constitute	a	multi-billiondollar	industry.	Although	botanicals	are	sold	as	dietary	supplements	or	ethnic	traditional	medicines,	 

herbal	formulations	are	not	subjected	to	FDA	premarket	approval	to	ensure	their	safety		 

or	efficacy.	 

National Toxicology Program 11 
  

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Current Directions 

The	NTP is planning or is conducting research on several medicinal herbs and compounds found 	 

in	herbs	(listed	in	Table	2)	to	examine	toxic	effects	associated	with	exposures	to	high	acute	doses	and	 

chronic	low	doses,	including	carcinogenicity,	reproductive	toxicity,	neurotoxicity,	and	immunotoxicity.	 

NTP	studies	include	both	traditional	toxicological	research	and	studies	to	understand	how	effects		 

might	occur.	 

Table 2 Herbals and Herbal Components under Study by the NTP 

Aloe vera gel Widely used for centuries as a treatment for minor burns and is 

increasingly being used in products for internal consumption. 

Bitter orange extract Bitter orange peel and its constituent synephrine are in dietary supplements 

used for weight loss. 

Black cohosh Used to treat symptoms of premenstrual syndrome, dysmenorrhea, 

and menopause. 

Bladderwrack A source of iodide used in the treatment of thyroid diseases and also found 

as a component of weight-loss preparations. 

Blue-green algae Claims to prevent cancer and heart disease and boost immunity. 

Use has been promoted for children to treat attention deficit disorder. 

Comfrey Used externally as an anti-inflammatory agent in the treatment of bruises, 

sprains, and other external wounds. Consumed in teas and as fresh leaves 

for salads. Based in part on NTP studies on the alkaloid components of comfrey, 

the FDA recommended that manufacturers of dietary supplements containing 

this herb remove them from the market. 

Echinacea purpurea extract Used as an immunostimulant to treat colds, sore throat, and flu. 

Ephedra Also known as Ma Huang.Traditionally used as a treatment for symptoms of 

asthma and upper respiratory infections. Often found in weight-loss and “energy” 

preparations, which usually also contain caffeine.The FDA has prohibited the 

sale of dietary supplements containing ephedra. 

Ginkgo biloba extract Ginkgo fruit and seeds have been used medicinally for thousands of years to promote 

improved blood flow and short-term memory, and to treat headache and depression. 

Ginseng and Ginsenosides Ginsenosides are thought to be the active ingredients in ginseng. Ginseng 

has been used as a laxative, tonic, and diuretic. 

Goldenseal root Traditionally used to treat wounds, digestive problems, and infections. 

Current uses include as a laxative, tonic, and diuretic. 

Green tea extract Used for its antioxidative properties. 

Kava kava extract A widely used medicinal herb with psychoactive properties sold as a calmative 

and antidepressant. A recent report of severe liver toxicity has led to restrictions 

of its sale in Europe. 

Milk thistle extract Used to treat depression and several liver conditions, including cirrhosis and 

hepatitis, and to increase breast milk production. 

Pulegone A major terpenoid constituent of the herb pennyroyal. Has been used as a 

carminative, insect repellent, emmenagogue, and abortifacient. 

Senna Laxative with increased use due to the removal of a widely used, 

chemical-stimulant type laxative from the market. 

Thujone Terpenoid found in a variety of herbs, including sage and tansy, and 

in high concentrations in wormwood. 

12 National Toxicology Program 
  

Current Directions 

Nanoscale Materials 

Nanotechnology	has	become	an	increasing	focus	of	U.S.	and	global	research	and	development	efforts.	 

As	with	many	technological	advances,	new	materials	are	created,	and	as	a	result,	the	potential	exists		 

for	new	and	unanticipated	exposures	for	which	the	impact	on	human	health	is	unknown.	The	NTP		 

has	begun	a	broad-based	research	program	to	address	potential	human	health	hazards	associated		 

with	the	manufacture	and	use	of	nanoscale	materials.	 

Nanoscale	materials	are	a	broadly	defined	set	of	substances	where	at	least	one	critical	dimension	is	less	 

than	100	nanometers	and	they	possess	unique	optical,	magnetic,	or	electrical	properties.	The	NTP’s	 

research	program	focuses	on	manufactured	nanoscale	materials	of	current	or	projected	commercial	 

importance.	Nanoscale	materials	can,	in	theory,	be	engineered	from	nearly	any	chemical	substance;	 

semiconductor	nanocrystals,	organic	dendrimers,	carbon	fullerenes	(“buckyballs”),	and	carbon	 

nanotubes	are	a	few	of	the	many	examples.	They	are	already	appearing	in	commerce	as	industrial	and	 

consumer	products,	and	as	novel	drug	delivery	formulations.	 

NTP	studies	will	evaluate	the	toxicological	properties	of	major	classes	of	nanoscale	materials	that	 

represent	a	cross	section	of	composition,	size,	surface	coatings,	and	physicochemical	properties.		 

The	NTP	will	investigate	fundamental	questions	concerning	if	and	how	nanoscale	materials	can		 

interact	with	biological	systems.	The	program	includes	studies	to	evaluate	the	biological	disposition	 

of	“quantum	dots”	(nanoscale	crystalline	fluorescent	semiconductors),	long-term	toxicology	studies	 

of	carbon-based	nanoscale	materials	(e.g.,	single-	or	multi-walled	nanotubes,	fullerenes),	and	 

phototoxicology	studies	of	representative	nanoscale	metal	oxide	particles	used	in	industrial	settings		 

and	consumer	products	(e.g.,	titanium	dioxide).	The	NTP	will	use	the	data	to	develop	mathematical	 

models	to	predict	the	absorption,	distribution,	metabolism,	and	elimination	of	nanoscale	materials		 

in	humans.	The	NTP	has	also	established	a	Nanotechnology	Working	Group	under	the	NTP	Board		 

of	Scientific	Counselors	to	bring	interested	parties	together	to	learn	about	this	initiative. 

Safe Drinking Water 

More	than	200	million	Americans	are	estimated	to	use	municipally	treated	drinking	water,	so	the	 

availability	of	safe	drinking	water	is	of	enormous	importance	to	public	health.	Many	agents	occur		 

(1)	naturally	in	water	(e.g.,	arsenic,	aluminum),	(2)	because	of	contamination	(e.g.,	methyl	tert-butyl	 

ether	and	other	gasoline	additives,	pesticides,	organic	tin	compounds),	or	(3)	with	environmental	 

changes	(e.g.,	cyanobacterial	toxins	from	algal	blooms	in	surface	waters).	The	NTP	is	designing		 

long-term	toxicology	and	toxicokinetic	studies	on	several	of	these	agents,	including	aluminum	 

complexes,	organic	tin	compounds,	and	the	two	most	common	cyanobacterial	toxins		 

(microcystin-LR	and	cylindrospermopsin).	 

Because	of	concerns	by	a	number	of	California	legislators,	the	California	Environmental	Protection	 

Agency,	and	the	California	Health	and	Human	Services	Agency,	the	NTP	is	studying	the	potential		 

of	hexavalent	chromium	in	drinking	water	to	cause	cancer.	Hexavalent	chromium	compounds	rarely	 

occur	naturally	and	are	typically	associated	with	industrial	sources.	Hexavalent	chromium	is		 

an	established	human	carcinogen	in	certain	occupational	settings,	presumably	as	a	result	of	inhalation	 

exposure.	Data	currently	available	on	the	chronic	toxicity	and	carcinogenicity	of	hexavalent	chromium	 

given	orally	are	not	sufficient	to	establish	or	characterize	any	hazard	for	it	in	the	water	supply.		 

NTP	studies	include	both	short-	and	long-term	administration	of	hexavalent	chromium	to	laboratory	 

animals	(sodium	dichromate	dihydrate	in	drinking	water),	as	well	as	studies	on	tissue	absorption	of	 

hexavalent	chromium.	 

National Toxicology Program 13 
  

Current Directions 

Occupational Exposures 

The	NTP	is	coordinating	an	effort	between	the	NIEHS	and	NIOSH	to	better	understand	worker	 

exposures,	educate	workers,	and	identify	occupational	health	research	gaps.	Current	efforts	are	 

addressing	worker	exposure	to	welding	fumes,	abrasive	blasting	materials,	and	metalworking	fluids.	 

Studies	of	diseases	in	workers	suggest	that	occupational	exposure	to	welding	fumes	may	cause	adverse	 

health	effects.	More	information	is	needed	to	evaluate	the	relationship	between	timing	and	amount		 

of	exposure	and	the	adverse	effects	that	result,	and	to	understand	the	specific	causes	of	these	effects.		 

The	NIOSH	has	constructed	a	computer-controlled,	automated	robotic	system	to	generate	tightly	 

controlled,	well-characterized	welding	fumes,	for	investigating	fumes	caused	by	different	welding	 

processes	and	materials.	These	studies	will	examine	the	physical	and	chemical	composition	of	the	 

generated	fumes	and	gases,	as	well	as	evaluate	which	exposure	conditions,	or	welding	processes		 

and	materials	cause	acute	biological	responses	in	laboratory	animals.	 

Alternatives	to	silica	sand	for	abrasive	blasting	are	frequently	recommended	to	reduce	workers’		 

risk	for	acquiring	fibrotic	lung	disease	and	cancer.	NIOSH	recommends	the	use	of	coal	slag,		 

garnet,	steel	grit,	crushed	glass,	and	specular	hematite	as	safe	alternatives	to	silica	sand	for	abrasive	 

blasting.	The	NTP	will	evaluate	the	relative	effects	of	these	alternatives	for	causing	lung	disease,		 

and	NIOSH	will	use	this	information	as	guidance	for	developing	exposure	limits	for	workers.	 

Millions	of	gallons	of	metalworking	fluids	are	used	each	day	in	industry	for	cutting,	milling,		 

drilling,	stamping,	and	grinding,	and	as	a	result,	workers	potentially	are	exposed	to	a	wide	variety		 

of	formulations	through	their	skin	and	in	the	air	they	breathe.	The	NTP	will	evaluate	the	acute	 

and	long-term	health	effects	of	several	commercial	products	in	laboratory	animals.		 

The	NIOSH	is	planning	a	National	Exposures	at	Work	Survey	that	will	be	conducted	in	a	nationally	 

representative	sample	of	workplaces	across	all	industries,	starting	with	the	health	services	industry.		 

This	survey	will	collect	data	on	chemical,	physical,	and	biological	agents	to	which	workers	could		 

be	exposed,	as	well	as	data	on	ways	to	control	exposure,	and	health	and	safety	practices.		 

Information	from	this	initiative	will	be	used	to	educate	workers,	identify	occupational	health		 

knowledge	gaps,	and	help	target	areas	where	research	is	likely	to	reduce	workplace	illness. 

DNA-Based Products 

DNA-based	therapies	are	being	developed	to	treat	a	wide	range	of	human	diseases.	However,	by		 

their	very	nature,	they	pose	a	risk	of	interacting	with	the	host’s	genes,	or	disrupting	normal	cellular	 

processes	in	unexpected,	unpredictable,	and	potentially	harmful	ways.	Examples	of	DNA-based	 

products	include	(1)	vaccines	against	viruses	and	bacteria	that	have	been	made	from	plasmid	DNA,		 

(2)	synthetic	oligonucleotides	to	modulate	gene	expression,	and	(3)	viral	carriers	for	gene	therapy.		 

The	FDA	has	only	limited	authority	to	require	evaluation	of	long-term	effects	of	these	therapies.	 

Presently,	the	NTP	is	collaborating	with	the	FDA	and	sister	NIH	institutes	to	study	the	safety	of		 

DNA-based	products.	These	studies	address	lifelong	risks	presented	by	their	use	and	the	potentials		 

for	reproductive	toxicities,	for	transmission	of	altered	genetic	material	to	subsequent	generations,		 

and	for	DNA-based	products	to	cause	autoimmune	disease	or	immune	dysfunction.	 

14 National Toxicology Program 
  

Current Directions 

Polybrominated Flame Retardants 

The	NTP	is	studying	how	exposure	to	polybrominated	flame	retardants	might	affect	human	health.	 

The	class	of	brominated	flame	retardants	called	polybrominated	diphenyl	ethers	(PBDE)	is		 

structurally	similar	to	the	dioxin-like	polychlorinated	biphenyls	raising	concern	for	carcinogenic	 

potential	and	developmental	toxicity.	In	addition,	there	is	evidence	that	they	similarly	accumulate	 

in	human	and	animal	tissues.	The	substances	under	evaluation	include	the	PBDE	isomers	found	in	 

DE-71,	the	most	widely	used	commercial	formulation	of	a	PBDE-based	flame	retardant,	as	well	as	 

two	other	brominated	flame	retardants:	tetrabromobisphenol	A	and	tetrabromobisphenol	A-bis	(2,3­

dibromopropyl)	ether. 

Perfluorinated Compounds 

Perfluorinated	compounds	or	their	chemical	precursors	have	been	used	since	the	1950s	as	surfactants	 

and	emulsifiers	in	commercial	products,	including	stain	or	water	protectors	for	carpets,	textiles,	auto	 

interiors,	camping	gear,	and	leather,	and	in	food	packaging	and	other	paper	containers.	Perfluorinated	 

compounds	such	as	perfluorooctyl	sulfonate	(PFOS)	and	perfluorooctanoic	acid	(PFOA)	have	been	 

found	globally	in	human	tissues	and	the	environment.	They	are	persistent	in	the	environment,	resistant	 

to	heat	and	chemical	stress,	and	insoluble	in	both	water	and	oil.	Although	much	is	known	about	the	 

toxicity	of	PFOS	and	PFOA,	the	same	cannot	be	said	for	other	members	of	this	class.	For	this	reason,	 

the	NTP	is	collaborating	with	the	Environmental	Protection	Agency	(EPA)	to	study	perfluorinated	 

compounds	as	a	class,	including	several	perfluorinated	sulfonates	and	carboxylic	acids,	as	well	as	 

fluorotelomeric	alcohol	derivatives	(potential	precursors	of	perfluorinated	carboxylic	acids).	 

This	initiative	includes	studies	on	reproduction	and	development	in	laboratory	animals,	as	well		 

as	studies	to	characterize	how	these	chemicals	behave	inside	the	body	to	learn	whether	members	of	 

this	class	of	compounds	have	similar	modes	of	action.	The	NTP	will	explore	the	use	of	in vitro	assays	 

in	conjunction	with	information	from	studies	in	laboratory	animals	to	predict	adverse	responses	to	 

chemicals	within	this	class.	If	common	modes	of	action	exist	among	these	chemicals,	then	a	cumulative	 

risk	assessment	might	be	more	appropriate	than	individual	chemical	assessments	to	evaluate	the	health	 

effects	of	perfluorinated	compounds	in	the	environment.	 

	 

National Toxicology Program 15 
  

Evolving Strategies
 

Considering	the	large	number	of	chemicals	in	commercial	use,	the	NTP	must	continually	set	priorities	
 

and	develop	research	strategies	to	characterize	toxicants	and	identify	hazards	that	make	the	best	use	of	
 

available	resources.	Using	new	testing	strategies	that	provide	more	or	better	information	can	strengthen	
 

the	scientific	knowledge	on	which	regulatory	decisions	are	based.	The	NTP	core	agencies	develop	and	
 

validate	new	testing	methods,	and	university-based	researchers	also	participate	in	these	efforts	through	
 

NIEHS	extramural	grants.	
 

Many	testing	strategies	focus	on	more	rapid	screening	tests,	alternative	or	complementary	in vivo	tests	
 

for	rodent	bioassays,	and	less	use	of	two-year	rodent	studies	to	determine	toxicities.	Strategies	include	
 

molecular	screening	methods,	non-mammalian	test	species,	genetically	engineered	animal	models,	
 

genetically	engineered	in vitro	cell	systems,	microchip-based	genomic	technologies,	and	computer-based	
 

predictive	toxicology	models.	Such	techniques	can	provide	insight	into	the	molecular	and	biological	
 

events	associated	with	a	chemical’s	toxic	effect,	as	well	as	mechanistic	information	for	assessing	human	
 

risk.	They	can	also	help	clarify	dose-response	relationships,	make	species	comparisons,	and	identify	
 

sources	of	variations	among	individuals.	Below	are	brief	overviews	of	some	current	and	emerging	NTP	
 

initiatives	highlighting	new	research	tools.	
 

High Throughput Screening 

The	NTP	promotes	improvements	in	toxicology	test	methods	that	will	enhance	the	program’s	ability	
 

to	evaluate	the	large	number	of	substances	in	our	environment	that	potentially	pose	hazards	for	human	
 

health.	As	part	of	its	activities	to	implement	the	NTP	Roadmap,	the	NTP	seeks	to	identify	or	develop	
 

rapid,	mechanism-based	assays	that	can	be	used	to	screen	large	numbers	of	environmental	substances	
 

for	their	potential	biological	activity	(high	throughput	screening	or	HTS).	The	concept	of	HTS	is	based	
 

on	the	use	of	automated	processes	to	evaluate	hundreds	to	thousands	of	substances	rapidly	using	in 


vitro	systems.	The	NTP	hopes	to	use	the	data	from	HTS	assays	to	(1)	identify	mechanisms	of	action	for	
 

further	investigation,	(2)	develop	models	to	predict	how	substances	might	react	in	biological	systems,	
 

and	(3)	prioritize	substances	for	more	extensive	toxicological	evaluation.	The	HTS	initiative	will	also	
 

generate	the	scientific	information	and	understanding	needed	by	health	regulatory	agencies	to	make	
 

decisions	on	potentially	toxic	materials	in	order	to	protect	public	health.	The	NTP	is	currently	in	the	
 

process	of	identifying	specific	assays	to	include	in	the	HTS	program.
 

16 National Toxicology Program 
  

In	August	2005,	the	NTP,	through	the	NIEHS,	became	a	formal	participant	in	the	NIH	Molecular	 

Libraries	Initiative	(MLI),	part	of	the	NIH	Roadmap	for	Medical	Research.	Although	the	MLI	was	 

originally	conceived	as	a	strategy	to	help	the	HTS	initiative	identify	chemical	probes	for	use	in	medical	 

and	basic	science	research,	the	NTP	is	working	with	MLI	project	leaders	to	expand	the	effort	by	adding	 

toxicity	testing	capabilities.	Through	this	collaboration,	the	NTP	can	link	information	on	the	biological	 

activity	of	environment	substances,	generated	from	HTS	assays,	with	toxicity	effects	identified	in	the	 

NTP’s	toxicology	testing	program.	 

To	date,	the	NTP	has	provided	approximately	1,400	chemicals	to	the	MLI,	as	well	as	six	HTS		 

cell-based	screening	assays	(three	that	measure	steps	integral	to	apoptosis,	two	that	assess	cytotoxicity,	 

and	one	that	measures	cell	membrane	P-glycoprotein	activity),	and	is	working	to	identify	other	 

commercially	available	HTS	assays	that	can	be	adapted	to	a	robotics-based	system.	Data	collected		 

on	these	chemicals	from	the	HTS	assays	will	be	maintained	in	a	database	accessible	to	the	NTP	and		 

the	MLI	for	future	analysis.	To	help	guide	this	process,	the	NTP	sponsored	the	HTS	Assays	Workshop	 

on	December	14-15,	2005,	to	discuss	the	usefulness	of	this	technology	for	the	NTP	and	toxicology. 

Caenorhabditis elegans 

The	NTP	is	interested	in	developing	rapid,	sensitive,	and	specific	tests	for	screening	environmental	 

agents.	A	current	focus	is	the	nematode	Caenorhabditis elegans (C. elegans).	The	NTP	is	investigating		 

the	response	of	C. elegans	when	exposed	to	known	or	suspected	toxicants	and	is	monitoring	the		 

effects	of	these	toxicants	on	its	growth,	size,	reproduction,	and	movement.	The	goal	is	to	determine		 

the	possibility	of	using	the	nematode	as	a	practical	and	efficient	model	in	toxicology	studies.		 

The	C. elegans	system	has	now	been	used	to	measure	the	toxicological	effects	of	transition	metals,	 

common	laboratory	solvents,	chemical	oxidants,	and	organochlorine	pesticides.	A	publicly	accessible	 

database	is	currently	under	construction	to	share	the	results	from	the	C. elegans	studies. 

NTP Research Databases 

A	primary	goal	of	the	NTP	is	to	evaluate	agents	of	public	concern	for	their	potential	toxicity	or	 

carcinogenicity.	Some	studies	address	general	toxic	effects	in	laboratory	animal	species,	whereas	others	 

focus	on	specific	immune,	neurological,	reproductive,	and	developmental	effects.	Data	from	general	 

toxicology	and	carcinogenicity	studies	are	publicly	available	on	the	NTP	website	(http://ntp.niehs.nih. 

gov).	The	NTP	is	expanding	the	public’s	access	to	its	data	to	include	all	study	types	(general	toxicology,	 

carcinogenesis,	genetic	toxicity,	and	organ	systems).	The	NTP	provides	access	to	the	data	in	a	common	 

National Toxicology Program 17 
  

 

 

 

 

 

 

Evolving Strategies 

format	using	web-based	applications	that	allow	users	to	query	data,	conduct	simple	statistical		 

manipulations,	and	export	the	information.	Basic	tools	are	available	on	the	website	to	allow		 

users	to	search	for	studies	on	specific	substances	and	retrieve	data	for	individual	animals.		 

The	NTP	is	also	developing	tools	for	conducting	systematic	searches	of	specific	effects	or		 

chemicals,	both	within	and	across	studies.	This	type	of	search	will	allow	comparison	of	effects		 

among	individual	chemicals	or	classes	of	chemicals. 

	 

Magnetic Resonance Imaging 

Traditionally	in	NTP	toxicology	and	carcinogenicity	studies,	lesions	are	evaluated	with		 

conventional	optical	microscopy	of	collected	tissue	samples.	Representative	samples	are	collected		 

because	examining	all	the	tissue	involved	is	impractical.	Because	of	recent	advances	in	the	technology	 

for	imaging,	magnetic	resonance	imaging	(MRI)	of	the	entire	body	at	microscopic	resolution	is	now	 

possible.	The	NTP	is	investigating	MRI	for	imaging	laboratory	animals	(see	Figure	3).	MRI	microscopy	 

is	three-dimensional,	can	examine	the	same	specimens	at	different	angles,	and	measures	the	volume		 

of	tissues	and	organs.	MRI	of	live	animals	permits	acquisition	of	imaging	data	at	different	times		 

over	an	animal’s	lifetime.	Because	the	images	are	digital,	web-based	viewing	is	easier.	 

MRI	is	a	noninvasive	technique	that	will	permit	the	NTP	to	perform	a	more	complete	and	thorough	 

examination	of	tissues	and	organs	from	test	animals	without	destroying	the	samples,	and	may	also	 

allow	more	information	to	be	gathered	from	studies	than	before.	Anticipated	uses	include	monitoring	 

lesions	and	examining	the	morphology	and	functionality	of	genetically	engineered	mice.	The	NTP	 

has	completed	pilot	studies	of	birth	defects	and	developmental	neurotoxicity	studies	and	is	currently	 

completing	a	pilot	study	to	monitor	long-term	the	development	of	liver	tumors	by	in vivo	images	of	 

mice	over	time.	 

Risk Assessment Methodology 

Risk	assessment	involves	using	scientific	information	to	determine	whether	exposures	to	agents	in	 

the	environment	or	workplace	are	hazardous	to	the	health	of	individuals	or	populations,	and	if	so,	to	 

what	extent.	Mathematical	models	that	accurately	represent	physiological	and	biochemical	processes	 

in	laboratory	animals	and	humans	can	provide	a	scientifically	sound	basis	for	using	data	from	studies	 

Figure 3 MRI Microscopy of Mice with Multiple Small Liver Tumors 

A. Transverse MRI slice through the liver of a live mouse. Spinal cord is at 6 o’clock. 

Liver tumors are circled. St = stomach. 

B. Transverse MRI slice through the liver of a mouse after perfusion fixation. 

Liver tumors are circled. St = stomach. 

C. Dorso-ventral slice through the liver of the same mouse after perfusion fixation. 

Multiple liver tumors are circled. St = stomach. Ce = cecum. S = small intestines. 

18 National Toxicology Program 
  

Evolving Strategies 

in	animals	to	determine	if	and	how	an	exposure	might	cause	health	effects	in	humans.	Physiologically	 

based	pharmacokinetic	(PBPK)	models	measure	the	biological	processes	of	absorption,	distribution,	 

metabolism,	and	elimination	of	an	agent	in	animals	or	humans	(Figure	4).	The	NIEHS	continues	to	 

develop	PBPK	models	to	evaluate	relationships	between	environmental	exposures	and	carcinogenicity,	 

and	developmental	and	reproductive	toxicities	(Table	3).	PBPK	models	are	often	included	in	NTP	 

Technical	Reports	or	are	published	in	the	peer-reviewed	literature.	 

Toxic Equivalency Factors 

2,3,7,8-Tetrachlorodibenzo-p-dioxin	(TCDD)	and	dioxin-like	compounds	comprise	a	large	class	of	 

structurally	related	environmental	contaminants	that	include	some	polychlorinated	biphenyls	(PCBs),	 

as	well	as	polychlorinated	dibenzodioxins	and	polychlorinated	dibenzofurans.	These	are	persistent	 

substances	that	remain	in	human	tissues	and	in	the	environment	for	extended	periods	of	time.	TCDD,	 

a	known	human	carcinogen,	and	other	dioxin-like	compounds	bind	to	the	same	aryl	hydrocarbon	 

receptor	(AhR).	Evaluating	effects	of	exposure	to	mixtures	of	these	compounds	is	more	complex	than	 

evaluating	exposures	to	individual	compounds.	The	Toxic	Equivalency	Factor	(TEF),	an	approach	 

established	by	the	World	Health	Organization	(WHO),	has	been	widely	accepted	as	the	best	method	to	 

evaluate	potential	health	risks	associated	with	exposure	to	mixtures	of	dioxin-like	compounds.	The	TEF	 

approach	ranks	the	toxicity	of	a	dioxin-like	compound	relative	to	the	most	potent	dioxin	TCDD.	 

Figure 4 Physiologically Based Pharmacokinetic Model Arterial Blood 

Venous Blood 

GI Lumen 

GI Blood 

GI Tract 

Liver Blood 

Liver Metabolism 

Fat Blood 

Fat 

Kidney Blood 

Kidney 

Oral Dose 

This model represents the uptake, distribution, and metabolism of an environmental agent administered orally. 

National Toxicology Program 19 
  

Evolving Strategies 

Table 3 Substances with PBPK Models Developed by the NTP 

Anthraquinone 

Butadiene 

Bromochloroacetic acid 

Bromodichloromethane 

Chromium picolinate monohydrate 

Decalin 

Dibromoacetic acid 

Dichloroacetic acid 

p,p’-Dichlorodiphenyl sulfone 

Divinylbenzene 

2,2',4,4',5,5'-Hexachlorobiphenyl 

Isoprene 

Melatonin 

Mercury 

Methyleugenol 

2-Methylimidazole 

4-Methylimidazole 

Naphthalene 

3,3',4,4',5-Pentachlorobiphenyl 

2,3,4,7,8-Pentachlorodibenzofuran 

PCB mixtures 

Pentabromodiphenyl oxide 

Primidone 

Propylene glycol mono-t-butyl ether 

Sodium nitrite 

Sodium dichromate dihydrate 

2,3,7,8-Tetrachlorodibenzo-p-dioxin 

Urethane 

The	NTP	evaluated	the	TEF	approach	in	its	long-term	toxicology	and	carcinogenicity	studies	by		 

testing	TCDD,	3,3',4',4',5-pentachlorobiphenyl	(PCB	126),	and	2,3,4,7,8-pentachlorodibenzofuran,	 

individually	and	in	combination	with	each	other.	Dose-response	analyses	showed	that	for	liver,	lung,	 

and	oral	mucosal	tumors,	effects	for	doses	of	any	one	of	the	three	individual	compounds	were	the	same	 

as	for	a	similar	potency-adjusted	dose	of	the	mixture.	Also,	the	tumor	response	by	dose	for	the	mixture	 

could	be	predicted	by	combining	the	effects	of	potency-adjusted	doses	of	the	individual	chemicals.	This	 

evaluation	affirmed	the	need	to	base	health	standards	on	mixtures	rather	than	on	single	chemicals	and	 

supported	the	appropriateness	of	assuming	that	the	effects	of	dioxins	should	be	added	together	when	 

using	TEFs	for	cancer	risk	assessments	for	dioxins.	 

Humans	are	exposed	to	mixtures	of	not	only	dioxin-like	PCBs	but	also	PCBs	that	have	either	weak	or	 

no	dioxin-like	activity.	The	TEF	scheme	deals	only	with	PCBs	with	dioxin-like	activity	and	assumes	 

that	there	is	no	interaction	between	these	and	the	non-dioxin-like	PCBs.	The	NTP	is	currently	 

addressing	interactions	between	PCBs.	The	results	from	studies	of	the	non-dioxin-like	PCB	153	 

(2,2',4,4',5,5'-hexachlorobiphenyl)	in	combination	with	PCB	126	indicate	that	the	potency	of	PCB	126	 

can	be	both	increased	and	decreased,	depending	upon	the	tumor	endpoint	examined,	by	co-exposure	 

with	PCB	153.	Studies	to	evaluate	how	the	weak-dioxin	PCB	118	(2,3',4,4',5-pentachlorobiphenyl)	 

affects	the	potency	of	PCB	126	are	ongoing.	 

Other	compounds,	in	addition	to	dioxins,	furans,	and	PCBs,	also	have	the	ability	to	bind	to	the	AhR,	 

but	are	not	currently	included	in	the	WHO	TEF	scheme.	The	NTP	is	evaluating	such	compounds	 

with	weak-dioxin-like	activity	(including	polychlorinated	naphthalenes,	tetrachloroazobenzene,	 

hexachlorobenzene,	and	indole-3-carbinol)	to	determine	if	they	have	chronic	toxicological	and	 

carcinogenic	effects	similar	to	those	of	TCDD,	which	would	argue	for	their	inclusion	in	dioxin		 

cancer	risk	assessments. 

Transgenic Animals 

For	more	than	three	decades,	the	NTP	has	conducted	studies	in	laboratory	rodents	to	identify	 

carcinogens	thought	to	pose	risks	to	human	health.	Genetically	engineered	animal	models	based		 

on	new	gene	technologies	are	being	evaluated	as	alternatives	or	complements	to	rodent	bioassays.	 

Genetically	altered	or	transgenic	mouse	models	carry	activated	oncogenes	or	inactivated	tumor	 

20 National Toxicology Program 
National Toxicology Program    3

Evolving Strategies 

suppressor	genes	known	to	be	involved	in	neoplastic	(tumor-causing)	processes	in	both	humans	and	 

rodents.	This	trait	may	allow	these	mice	to	respond	or	show	the	effects	of	carcinogens	more	quickly		 

and	more	reliably	than	conventional	rodent	strains.	Target	or	reporter	genes	in	the	animals	also	allow	 

direct	molecular	and	cellular	analysis	of	a	chemical’s	effects	and	can	provide	additional	mechanistic	 

information	about	its	mode	of	action.	 

The	NTP	sought	input	from	its	advisory	groups	and	the	public	about	the	usefulness	of	a	number		 

of	transgenic	rodent	models	for	short-term	studies	of	carcinogenicity	[p53(+/–),	Tg.AC	(v-Ha-ras),		 

and	RasH2].	In	general,	there	is	support	for	using	the	p53(+/-)	and	RasH2	models	to	evaluate	the	 

carcinogenic	potential	of	chemical	or	physical	agents.	The	NTP	will	continue	to	consider	transgenic	 

models	when	designing	the	testing	strategy	for	substances	under	study.	As	understanding	increases		 

of	the	complex	signaling	pathways	that	are	turned	on	or	off	during	carcinogenesis,	the	NTP	will	be	able		 

to	select	transgenic	animal	models	that	best	mimic	human	tissue	responses.	This	strategy	should		 

provide	a	firmer	foundation	for	applying	hazard	data	from	animals	to	humans.	 

Toxicogenomics 

New	molecular	technologies	have	brought	the	NTP	into	the	arena	of	toxicogenomics,	a	new	scientific	 

field	that	examines	how	the	entire	genetic	structure,	or	genome,	is	involved	in	an	organism’s	response		 

to	environmental	toxicants.	Toxicogenomics	applies	knowledge	of	genetics	to	environmental	medicine	 

by	studying	the	effect	of	toxicants	on	gene	activity	and	specific	proteins	produced	by	genes.	It		 

combines	information	from	studies	of	genomic-scale	messenger	RNA	profiling	(by	microarray	analysis),		 

cell-wide	or	tissue-wide	protein	profiling	(proteomics),	genetic	susceptibility,	and	computational		 

models.	This	information	helps	illustrate	how	interactions	between	genes	and	the	environment	affect	 

the	onset	and	progression	of	disease.	This	field	could	revolutionize	environmental	health,	drug	safety,	 

and	risk	assessment.	 

Initial	efforts	by	the	NTP	include	studying	variables	that	affect	gene	expression	in	the	liver.	To	date,	 

the	NTP	has	studied	individual	variation	in	hepatic	gene	expression	in	male	rats,	including	the	effect	 

of	circadian	rhythm,	the	effect	of	age,	variability	due	to	conducting	studies	on	different	days	and	 

in	different	laboratories,	and	the	effect	of	feed	(pellets	or	mash)	on	hepatic	gene	expression.	This	 

information	is	crucial	in	understanding	how	environmental	agents	may	affect	the	disease	process.	The	 

study	of	agents	that	might	promote	or	cause	cancer	is	one	of	the	more	time-consuming	and	costly	NTP	 

efforts.	Therefore,	several	studies	have	been	launched	to	determine	whether	the	analyses	of	hepatic	gene	 

expression	may	allow	earlier	detection	and	greater	understanding	of	the	role	of	the	environment	on	 

the	onset	and	progression	of	hepatocellular	cancer.	The	NTP	is	also	evaluating	gene	expression	after	 

exposure	to	substances	known	to	affect	the	immune	system	and	natural	products	known	to	cause	cancer	 

in	humans. 

National Toxicology Program 21 
  

Centers 

NTP Center for Phototoxicology 

The	NTP	Center	for	Phototoxicology	(NCP),	established	in	2000,	conducts	research	on	how	 

light	affects	the	toxicology	and	carcinogenicity	of	substances	nominated	to	the	NTP	and	on	the	 

mechanisms	that	underlie	these	effects.	Current	research	initiatives	are	described	on	page	11	under	 

“Phototoxicology.”	Research	in	this	area	is	very	important	because	of	the	public’s	increasing	exposure	to	 

UV	radiation	or	sunlight	through	more	frequent	use	of	tanning	booths	and	more	leisure	time	spent	in	 

outdoor	activities.	 

The	NCP’s	state-of-the-art	laboratory	can	study	the	potential	toxic	or	carcinogenic	effects	of	a	test	 

substance	in	combination	with	UV	or	visible	radiation	from	several	light	sources.	The	NCP	also	 

conducts	mechanistic	studies	to	learn	how	these	effects	might	occur.	The	laboratory	can	simulate	 

natural	sunlight	using	filtered	6.5-kilowatt	xenon-arc	lamps,	which	enable	researchers	to	duplicate	 

human	exposure	conditions.	The	facility	can	also	perform	studies	using	light	from	different	types	of	 

fluorescent	tubes,	such	as	those	used	in	fluorescent	lamps	and	suntan-bed	lamps.	 

The	NTP	Board	of	Scientific	Counselors	advises	the	NCP	on	its	programs	and	priorities.	Substances	 

selected	for	testing	are	nominated	directly	from	the	FDA	and	from	outside	submissions	to	the	NTP.		 

The	FDA’s	Chemical	Selection	Working	Group	prioritizes	nominations	and	forwards	them	to	the		 

NTP	for	formal	consideration	in	its	nomination	and	selection	process.	More	information	about	the	 

NCP	is	available	by	contacting	Dr.	Paul	C.	Howard,	director,	NCP	(for	contact	information,	see		 

inside	back	cover). 

	 

Center for the Evaluation of Risks to Human Reproduction 

Established	in	1998,	the	NTP’s	Center	for	the	Evaluation	of	Risks	to	Human	Reproduction	(CERHR)	 

serves	as	an	environmental	health	resource	to	the	public,	and	to	regulatory	and	health	agencies.	The	 

NTP	Board	of	Scientific	Counselors	advises	the	CERHR	on	its	processes,	priorities,	and	direction.	 

The	CERHR	provides	scientifically	based,	uniform	assessments	of	the	potential	for	adverse	effects	 

on	reproduction	and	development	caused	by	human	exposure	to	chemicals.	It	follows	a	formal,	open	 

process	for	nomination,	selection,	and	review	of	chemicals,	and	public	input	is	encouraged.	The	 

CERHR	selects	chemicals	for	review	based	on	several	factors,	including	how	much	is	produced,		 

how	many	people	are	exposed,	public	concern	about	the	chemical	hazard,	and	published	evidence		 

of	reproductive	or	developmental	toxicities.	 

22 National Toxicology Program 
  

Assessed	through	rigorous	evaluations	by	independent	scientific	panels	in	public	forums,	these	 

evaluations	are	intended	to: 

•	Interpret	scientific	evidence	and	provide	information	to	the	public	about	the	strength		 

of	the	evidence	that	a	given	exposure	or	circumstance	poses	a	hazard	to	reproduction,		 

or	to	the	health	and	welfare	of	children. 

•	Provide	regulatory	agencies	with	objective	and	scientifically	sound	assessments	of	data		 

related	to	the	reproductive/developmental	health	effects	associated	with	exposure	to		 

specific	chemicals	or	classes	of	chemicals,	including	descriptions	of	any	uncertainties		 

associated	with	these	assessments.	 

•	Identify	knowledge	gaps	to	help	establish	research	and	testing	priorities.	 

Chemicals	reviewed	to	date	by	the	CERHR	expert	panels	are	listed	in	Table	4.	Future	reviews		 

include	genistein	and	soy	formula,	bisphenol	A,	and	hydroxyurea. 

The	NTP-CERHR	Monograph	series	reports	the	findings	for	chemicals	evaluated	by	the	CERHR.		 

Each	monograph	includes	the	NTP	Brief,	the	Expert	Panel	Report,	and	public	comments	on	the		 

Expert	Panel	Report.	The	brief	gives	the	NTP’s	interpretation	of	the	potential	for	the	chemical	to		 

cause	adverse	reproductive	and/or	developmental	effects	in	exposed	humans,	and	is	based	on	the		 

Expert	Panel	Report,	public	comments,	and	new	information	available	after	the	expert	panel		 

meeting.	NTP-CERHR	monographs	are	transmitted	to	appropriate	federal	and	state	agencies		 

and	are	made	available	to	the	public.	Expert	Panel	Reports	and	NTP-CERHR	monographs	are		 

posted	on	the	CERHR	website	(http://cerhr.niehs.nih.gov)	and	are	available	in	hard	copy	and		 

CD-ROM	from	the	CERHR.	 

The	CERHR	conducts	workshops	bringing	together	experts	to	discuss	important	topics	relative	to	 

the	effects	of	environmental	agents	on	reproduction	and	development.	The	CERHR	website	has	 

information	on	various	environmental	exposures	and	their	potential	to	affect	pregnancy	and		 

child	development,	as	well	as	links	to	other	resources.	 

The	CERHR	welcomes	nominations	of	chemicals	for	review,	as	well	as	scientists	for	its	registry		 

of	experts.	Information	about	the	CERHR	and	the	nomination	process	is	available	from	its	website		 

or	by	contacting	Dr.	Michael	Shelby,	director,	CERHR	(for	contact	information,	see	inside	back	cover).	 

National Toxicology Program 23 
  

                        

                          

                    

                   

               

                     

                           

   

                 

               

                     

                     

                    

                   

                          

                       

                          

       

                             

                 

                 

                         

                                 

   

                       

                 

 

 

Centers 

Table 4 Chemicals Reviewed by CERHR Expert Panels 

Acrylamide Used in production of polyacrylamide that is used in water treatment, pulp 

and paper production, and mineral processing. Also used in the synthesis of dyes, 

adhesives, contact lenses, soil conditioners, and permanent press fabrics and 

in electrophoresis. 

Amphetamines Central nervous system stimulants. Amphetamine is indicated for the treatment of attention deficit hyperactivity disorder (ADHD) and narcolepsy. Methamphetamine is indicated for the treatment of ADHD and for short-term treatment of obesity. 

1-Bromopropane Solvent in spray adhesives and cold bath degreaser. Potential use as a replacement for 

ozone-depleting hydrochlorofluorocarbons and chlorinated solvents. 

2-Bromopropane Contaminant in 1-bromopropane. Used in synthesis of pharmaceuticals and dyes. 

Di-(2-ethylhexyl) High production volume chemical. Used in polyvinyl chloride-based consumer 

phthalate products such as building products, car products, children’s products (but not 

in toys intended for mouthing), clothing, food packaging, and in medical devices. 

Ethylene glycol High production volume chemical used chiefly in the production of polyester 

compounds and widely used as antifreeze for heating and cooling systems. 

Fluoxetine Used primarily as an antidepressant in adults; is approved for use in children 

7 to 17 years old. Also used to treat premenstrual dysphoric disorder. 

Methanol Used primarily in chemical synthesis and racecar fuels. Has potential use as a 

vehicle fuel or fuel additive. 

Methylphenidate A central nervous system stimulant approved by the FDA for the treatment of ADHD and 

narcolepsy in persons 6 or more years of age. 

Phthalates (7)* Primary plasticizers in a wide range of polyvinyl chloride-based consumer 

products. 

Propylene glycol Used in production of polyester resins, such as antifreeze and de-icing solution, and 

in paints and coatings. Also approved for use as a food additive and for use in some 

drugs and cosmetics. 

Styrene High production volume chemical used in the production of polystyrene resins. Is found 

in foam cups, dental fillings, ion exchange filters, and construction materials. 

* butyl benzyl phthalate, di(2-ethylhexyl) phthalate, di-isodecyl phthalate, di-isononyl phthalate, di-n-butyl phthalate, di-n-hexyl phthalate, and 


di-n-octyl phthalate
 

NTP Interagency Center for the Evaluation of Alternative Toxicological Methods 

Toxicity	testing	is	necessary	to	assess	the	hazards	and	safety	of	substances	in	our	environment.	 

Developing,	validating,	accepting,	and	harmonizing	new,	alternative,	and	revised	toxicological	 

test	methods	are	coordinated	throughout	the	federal	government	by	the	Interagency	Coordinating	 

Committee	on	the	Validation	of	Alternative	Methods	(ICCVAM).	Established	in	2000,	ICCVAM	 

consists	of	representatives	from	15	federal	agencies	(Table	5).	The	NTP	Interagency	Center	for	the	 

Evaluations	of	Alternative	Toxicological	Methods	(NICEATM)	provides	scientific	and	operational	 

support	for	ICCVAM	and	its	activities.	The	Scientific	Advisory	Committee	on	Alternative	Toxicological	 

Methods	(SACATM)	provides	advice	on	the	activities	of	NICEATM	and	ICCVAM.	 

NICEATM	and	ICCVAM	work	together	to	evaluate	new,	revised,	and	alternative	toxicological	test	 

methods	that	may	(1)	predict	human	health	risks	better,	(2)	save	time	and	money,	and	(3)	refine	(cause	 

less	pain	and	distress),	reduce,	or	replace	animal	use.	NICEATM	also	promotes	information	sharing	and	 

communication	among	government	agencies,	industry,	the	public,	and	the	international	community.	 

ICCVAM	has	a	formal	process	for	nominating	and	submitting	new,	revised,	and	alternative	 

toxicological	test	methods	for	evaluation.	Once	test	methods	are	accepted	for	evaluation,	NICEATM	 

and	ICCVAM	convene	independent,	scientific,	peer	review	panels	to	assess	their	usefulness	and	 

limitations.	Workshops	and	expert	panel	meetings	are	also	convened	to	(1)	evaluate	how	well	current	 

safety	assessment	methods	are	working,	(2)	identify	areas	needing	improved	or	new	methods,	(3)	assess	 

24 National Toxicology Program 
  

 

                    

            

                  

       

             

         

                   

                

         

                   

             

              

                  

               

                  

                            

       

     

   

       

   

       

   

         

       

     

           

           

           

       

         

Centers 

the	current	validation	status	of	new	methods,	and	(4)	recommend	appropriate	research,	development,	 

and	validation.	These	meetings	are	open	to	the	public	and	provide	an	opportunity	for	public	comment.	 

Meeting	reports,	public	comments,	and	ICCVAM	recommendations	on	the	scientific	validity	and	potential	 

acceptability	of	alternative	test	methods	are	forwarded	to	federal	agencies	for	their	consideration.	Each	 

agency	determines	the	regulatory	acceptability	of	a	method	according	to	its	own	statutory	mandates.	 

ICCVAM	also	works	to	achieve	international	acceptance	of	test	methods	that	it	finds	to	be	scientifically	 

valid	for	specific	uses.	Test	methods	evaluated	by	the	ICCVAM	process	or	those	under	consideration	for	 

review	are	listed	in	Table	6.	ICCVAM	has	developed	a	process	for	establishing	performance	standards	for	 

validated	and	accepted	test	methods.	These	standards	can	be	used	to	determine	the	acceptability	of	other	 

proposed	test	methods	that	are	based	on	similar	scientific	principles,	and	measure	or	predict	the	same	 

biological	or	toxic	effect.	 

More	information	about	NICEATM	and	ICCVAM,	meeting	schedules,	meeting	reports	and	minutes,	 

and	information	on	nominating	alternative	toxicological	methods	are	available	through	the	ICCVAM/ 

NICEATM	website	(http://iccvam.niehs.nih.gov)	or	by	contacting	Dr.	William	S.	Stokes,	director,	 

NICEATM	(for	contact	information,	see	inside	back	cover).	 

Table 5 ICCVAM 

• Agency for Toxic Substances and Disease Registry • Food and Drug Administration 

• Consumer Product Safety Commission • National Cancer Institute 

• Department of Agriculture • National Institute of Environmental Health Sciences 

• Department of Defense • National Institutes of Health 

• Department of Energy • National Library of Medicine 

• Department of the Interior • National Institute for Occupational 

• Department of Transportation • Safety and Health 

• Environmental Protection Agency • Occupational Safety and Health Administration 

Table 6 Test Methods Evaluated or under Consideration by ICCVAM 

Test Method 

Murine Local Lymph Node Assay 

Corrositex®, EpiDermTM, EPISKINTM, and 

Transcutaneous Electrical Resistance Assay 

Up-and-Down Procedure 

In vitro cytotoxicity methods 

In vitro androgen receptor and 

transcriptional activation assays 

In vitro estrogen receptor and 

transcriptional activation assays 

FETAX (Frog Embryo Teratogenesis Assay: 

Xenopus) 

Bovine Corneal Opacity and Permeability 

Test, Hen’s Egg Test-Chorioallanotoic 

Membrane Test, Isolated Chicken Eye Test 

Method or Chicken Enucleated Eye Test 

Method, and the Isolated Rabbit Eye Assay 

In vitro pyrogenicity test methods (PBMC/ 

IL-6, WB/IL-1, cryo WB/IL-1, WB/IL-6, MM6/IL-6) 

Regulatory Application 

Substitute for currently accepted guinea pig test methods for allergic 

contact dermatitis. Received regulatory acceptance by U.S. agencies 

in 1999 and adopted by the international Organisation for Economic 

Co-operation and Development in 2002. 

In vitro methods to determine dermal corrositivity. Corrositex® received 

regulatory acceptance by U.S. agencies in 2000. 

Alternative method for assessing acute oral toxicity and replacement for 

the conventional LD50 test for hazard classification testing. Received 

regulatory acceptance by U.S. agencies in 2003. 

Used to estimate doses for assessing acute systemic toxicity in animals. 

EPA’s Endocrine Disruptor Screening Program for identifying potential 

endocrine-disrupting chemicals. 

EPA’s Endocrine Disruptor Screening Program for identifying potential 

endocrine-disrupting chemicals. 

In vitro method to determine the developmental toxicity of chemicals 

and mixtures. 

In vitro methods to assess ocular corrosiveness and severe irritation. 

In vitro methods proposed to replace currently accepted tests that 

require the use of rabbits or an in vitro test that requires the use of 

horseshoe crabs. 

National Toxicology Program 25 
  

Report on Carcinogens
 The	Report	on	Carcinogens	(RoC)	is	prepared	every	two	years	in	response	to	Section	301	of	the	Public	
 

Health	Service	Act,	as	amended.	The	RoC	lists	all	substances	that	either	are	known	to	be	human	
 

carcinogens	or	may	reasonably	be	anticipated	to	be	human	carcinogens,	and	to	which	a	significant	
 

number	of	people	living	in	the	United	States	are	exposed.	The	secretary,	DHHS	delegated	responsibility	
 

for	preparing	the	RoC	to	the	NTP.	The	NTP	prepares	the	report	with	help	from	other	federal	health	and	
 

regulatory	agencies	and	nongovernmental	institutions.	
 

The	RoC	is	an	informational,	scientific,	and	public	health	document	identifying	and	discussing	agents,	
 

substances,	mixtures,	and	exposure	circumstances	that	may	pose	a	carcinogenic	hazard	to	human	health.	
 

It	compiles	relevant	and	useful	data	on	the	listed	substances,	including	carcinogenicity,	genotoxicity,	
 

and	biological	mechanisms	in	humans	and/or	animals,	the	potential	for	exposure	to	them,	and	federal	
 

regulations	to	limit	exposures.	
 

The	NTP	solicits	and	encourages	broad	participation	from	individuals	or	groups	interested	in	
 

nominating	agents,	substances,	mixtures,	or	exposure	circumstances	for	listing	in	or	delisting	(removal)	
 

from	the	RoC.	Anyone	may	submit	a	nomination	for	consideration.	The	preparation	and	review	process	
 

for	each	RoC	takes	about	three	years.	Review	of	the	nominations	for	listing	in	or	delisting	from		
 

the	RoC	follows	a	formal	process	that	includes	many	phases	of	scientific	peer	review	and	opportunities	
 

for	public	comment.	The	review	groups	evaluate	each	nomination	according	to	specific	RoC	criteria.		
 

The	NTP	director	evaluates	all	review	group	recommendations,	public	comments,	and	other	information	
 

in	developing	a	recommendation	to	the	secretary,	DHHS.	
 

The	11th	RoC	was	released	January	31,	2005,	and	is	available	on	the	NTP	website	(http://ntp.niehs.nih.
 

gov	and	select	“Report	on	Carcinogens”),	or	in	hard	copy	or	printed	text	from	Central	Data	Management	
 

(CDM)	(for	contact	information,	see	inside	back	cover).	Nominations	under	consideration	for	the	12th	
 

RoC	are	listed	in	Table	7.	
 

The	NTP	holds	public	meetings	to	gain	input	regarding	procedures	used	for	the	review	of	nominations	
 

for	listing	in	or	delisting	from	the	RoC	and	on	the	criteria	used	for	evaluation	of	the	nominations.	These	
 

meetings	provide	an	opportunity	for	the	public	to	present	its	views	to	the	NTP.	The	most	recent	public	
 

meeting	was	held	in	January	2004.	Information	concerning	this	meeting,	including	the	public	comments	
 

received,	the	meeting	transcript,	and	the	NTP	response	to	issues	identified	at	this	meeting,	is	posted	on	
 

the	NTP	website.	
 

26 National Toxicology Program 
  

 

 

 

 

Table 7 Nominations to the 12th Report on Carcinogens 

Review for possible listing 

Aristolochic acid 

Herbal remedies containing aristolochic acid 

Captafol 

Cobalt–tungsten carbide powders and hard metals 

Etoposide 

Etoposide in combination with cisplatin and bleomycin 

Metalworking fluids 

ortho-Nitrotoluene 

Riddelliine 

Styrene 

Teniposide 

Principle extract from Aristolochia sp. Is a mixture of nitrophenanthrene 

carboxylic acids. 

Used as a traditional Chinese herbal remedy to promote health, 

weight loss, and for a wide range of medical conditions. 

Fungicide widely used since 1961 for the control of fungal diseases in 

fruits, vegetables, and some other plants. Use in the United States was 

banned in 1999. 

Used to make cutting tools and wear-resistant products. 

A DNA topoisomerase II inhibitor used in chemotherapy for nonHodgkin’s lymphoma, small-cell lung cancer, testicular cancer, lymphomas, and a variety of childhood malignancies. 

Used to treat testicular germ cell cancers. 

Used to cool and lubricate tools and working surfaces in a variety of 

industrial machining and grinding operations. 

Used to synthesize agricultural and rubber chemicals, azo and sulfur 

dyes, and dyes for cotton, wool, silk, leather, and paper. 

A member of a class of toxic pyrrolizidine alkaloids found in some 

plants growing in western United States. Cattle, horses, and sheep 

ingest these plants and residues have been found in milk and honey. 

Used in the production of polystyrene, acrylonitrile-butadiene-styrene 

resins, styrene-butadiene rubbers and latexes, and unsaturated 

polystyrene resins. 

A DNA topoisomerase II inhibitor used mainly in the treatment of adult 

and childhood leukemia. 

Review for possible reclassification of listing 

Certain glass wool fibers 

Di-(2-ethylhexyl) phthalate 

Formaldehyde 

Used in thermal, electrical, and acoustical insulation, weatherproofing, 

and filtration media. Some special purpose glass wool fibers are used 

for high-efficiency air filtration media and acid battery separators. 

Used mainly as a plasticizer in flexible polyvinyl chloride (PVC) products. Plasticized PVC is used in many consumer items and building 

products such as floor tiles, furniture upholstery, shower curtains, table 

cloths, toys, and many other products, and in plastic medical devices. 

Used in the production of resins for use in different products including 

plastics, adhesives, and binders for wood products, pulp and paper, 

synthetic fibers, and in textile finishing. Also used as a disinfectant and 

preservative and as an intermediate for many industrial chemicals. 

More	information	about	the	RoC,	how	to	obtain	copies	of	the	report,	and	how	to	submit	a	nomination	 

for	listing	in	or	delisting	from	the	RoC,	is	available	through	the	NTP	website	or	by	contacting	 

Dr.	C.W.	Jameson,	director,	RoC	(for	contact	information,	see	inside	back	cover).	 

							 

National Toxicology Program 27 
  

Outreach 

Open	communication	with	federal	and	state	agencies,	industry,	academia,	advocacy	groups,	and	the	 

public	is	crucial	for	the	success	of	NTP	activities.	Partnerships	with	sister	federal	agencies	are	ongoing,	 

and	the	NTP	continues	to	collaborate	with	the	private	sector.	NTP	conferences	and	workshops	give	 

researchers,	regulators,	policy	makers,	and	the	public	the	chance	to	examine	issues	together,	exchange	 

information,	and	reach	agreement	on	future	directions	for	toxicology	and	risk	assessment.	 

The	NTP	is	interested	in	input	from	the	public	and	all	interested	parties	on	its	programs	and		
 

priorities.	Nominations,	inquiries,	and	comments	are	welcome	at	any	time.	The	NTP	Liaison		
 

and	Scientific	Review	Office	collects	input,	represents	the	program	through	exhibits	at	national		
 

and	international	meetings,	publishes	the	quarterly	newsletter	NTP Update,	and	oversees	the	
 

distribution	of	information	about	programs,	workshops,	initiatives,	and	other	projects.	In	addition,		
 

this	office	manages	scientific	peer	review	for	the	NTP	and	organizes	workshops	on	scientific	and		
 

public	health	topics.	General	inquiries	and	requests	for	information	can	be	directed	to	this	office		
 

(for	contact	information,	see	inside	back	cover).	
 

The	NTP	website	(http://ntp.niehs.nih.gov)	provides	searchable	access	to	NTP	activities	and	offers	 

access	to	information	about	the	NTP,	with	links	that	detail	and	highlight	ongoing	and	future	initiatives	 

and	the	NTP	centers.	The	NTP	distributes	testing	and	research	results,	program	plans,	and	other	 

publications	through	mailings,	Federal Register	announcements,	and	the	NTP	website.	Also,	individuals	 

can	subscribe	free	of	charge	to	the	NTP	listserv	by	registering	online	through	the	website	or	by	sending	 

e-mail	to	ntpmail-request@list.niehs.nih.gov	with	“Subscribe”	as	the	message.	The	NTP	listserv	notifies	 

subscribers	by	e-mail	about	the	release	of	new	NTP	publications	and	about	upcoming	events	such	as	 

advisory	committee	meetings,	peer	reviews,	expert	panel	meetings,	and	workshops.	 

The	Central	Data	Management	(CDM)	oversees	distribution	(on	request)	of	specific	chemical	study	
 

information	and	NTP	documents	including	the	NTP	Annual	Report,	NTP	study	status	reports,	
 

background	documents	for	chemicals	nominated	to	the	NTP	for	study,	and	copies	of	draft	NTP	
 

Technical	Reports,	NTP	Toxicity	Reports,	and	NTP	Genetically	Modified	Models	Reports.	To		
 

request	any	of	these	documents,	contact	the	CDM	(for	contact	information,	see	inside	back	cover).	
 

28 National Toxicology Program 
Contact Information 

Primary Contact: 

NTP Liaison and Scientific Review Office 

P.O. Box 12233, MD A3-01
 

Research Triangle Park, NC 27709
 

Telephone: (919) 541-0530
 

E-mail: liaison@starbase.niehs.nih.gov
 

Program Contacts: 

NTP Center for the Evaluation of Risks to 

Human Reproduction 

P.O. Box 12233, MD EC-32
 

Research Triangle Park, NC 27709
 

Telephone: (919) 541-3455
 

E-mail: cerhr@niehs.nih.gov
 

Website: http://cerhr.niehs.nih.gov
 

NTP Center for Phototoxicology 

NCTR/FDA, HFT-110
 

3900 NCTR Road
 

Jefferson, AR 72079
 

Telephone: (870) 543-7672
 

E-mail: phoward@nctr.fda.gov
 

Website: www.fda.gov/nctr/science/centers/phototoxicology
 

NTP Interagency Center for the Evaluation of 

Alternative Toxicological Methods 

P.O. Box 12233, MD EC-17
 

Research Triangle Park, NC 27709
 

Telephone: (919) 541-2384
 

E-mail: niceatm@niehs.nih.gov
 

Website: http://iccvam.niehs.nih.gov
 

Office of Chemical Nomination and Selection 

P.O. Box 12233, MD A3-01
 

Research Triangle Park, NC 27709
 

Telephone: (919) 541-5710
 

E-mail: ntpnomin@niehs.nih.gov
 

Report on Carcinogens 

P.O. Box 12233, MD EC-14
 

Research Triangle Park, NC 27709
 

Telephone: (919) 541-4096
 

E-mail: jameson@niehs.nih.gov
 

Central Data Management 

P.O. Box 12233, MD EC-03
 

Research Triangle Park, NC 27709
 

Telephone: (919) 541-3419
 

E-mail: cdm@niehs.nih.gov
 

National Toxicology Program 

NTP

Headquartered at the 

National Institute of Environmental Health Sciences 

National Institutes of Health 

P.O. Box 12233
 

Research Triangle Park, NC 27709
 

Website: http://ntp.niehs.nih.gov
 

Public Health Service 

U.S. Department of 

Health and Human Services 

National Toxicology Program 

Printed in 2006 on recycled paper