Because of their unique physicochemical properties, engineered nanoparticles have the potential to significantly impact respiratory research and medicine by means of improving imaging capability and drug delivery, among other applications. These same properties, however, present potential safety concerns, and there is accumulating evidence to suggest that nanoparticles may exert adverse effects on pulmonary structure and function. The respiratory system is susceptible to injury resulting from inhalation of gases, aerosols, and particles, and also from systemic delivery of drugs, chemicals, and other compounds to the lungs via direct cardiac output to the pulmonary arteries. As such, it is a prime target for the possible toxic effects of engineered nanoparticles. The purpose of this article is to provide an overview of the potential usefulness of nanoparticles and nanotechnology in respiratory research and medicine and to highlight important issues and recent data pertaining to nanoparticle-related pulmonary toxicity.

B a r ry S . L y n ch , D ou g la s W . B ry a n t , G ra h a m J . H ook , E a r le R . N est m a n n , a n d I a n C . M u n ro C a n Tox, I n c, M is s is s a u g a , O n t a r io, C a n a d a -M on och l or o-1 ,2 -p r op a n ed i ol (-M C P D ) i s a b y -p r od u ct f ou n d i n t r a ce a m ou n t s , gen er a l ly l es s t h a n 1 m g/ k g (<1 p p m ), in h y d rol yz ed v eget a b l e p r ot ein p r od u ced t h rou gh a cid h y d r ol y si s. I n a ch r on ic s t u d y w it h F 4 4 r a t s , h igh d os es of -M C P D p r od u ced ben ig n r en a l t u m or s i n bot h s ex es a n d L ey d i g-cell a n d m a m m a r y t u m or s in m a l es . 3-M C P D is gen ot ox i c in v it r o, b u t t h er e is n o ev id en ce of gen ot ox i ci t y in v i v o. T h er e is som e q u es t ion a b ou t t h e m ech a n is m res p on s ib le for t h e ca r ci n og en i ci t y of -M C P D in cer t a in sp eci es . H er e w e p r esen t a cr i t ica l r ev i ew of t h e t ox icol ogica l , m et a bol ic, a n d m ech a n i s t ic d a t a on -M C P D . O n t h e b a si s of t h is r ev i ew , t h e t u m or s r ep ort ed i n F 4 4 r a t s a r e concl u d ed t o h a v e d ev elop ed a s a r es u lt of n on gen ot ox i c m ech a n is m s a n d a re consi d ered n ot t o be relev a n t t o h u m a n s ex p os ed t o t r a ce a m ou n t s of -M C P D . T h i s con clu s ion w a s b a sed on t h e l a ck of ca r ci n ogen i ci t y of -M C P D in m ice or S p r a gu e-D a w ley r a t s ; t h e b en i gn n a t u r e of t h e t u m ors i n v ol v ed ; t h e d ep en d en ce of t h e L eyd i g-cell a n d m a m m a r y t u m or s on s p ecies-a n d st r a in -d ep en d en t m ech a n is m s in v ol v i n g ch r on ic ch a n ges i n h or m on e b a la n ce; t h e a ss oci a t i on of t h e ren a l t u m or s w i t h ch r on ic n ep h r op a t h y a n d n ep h r ot ox i ci t y ; a n d d if feren ces b et w een b a ct eri a l a n d m a m m a l ia n s ys t em s in t h e m et a b ol is m of -M C P D t h a t li k el y a ccou n t f or it s g en ot ox ic a ct iv it y i n cert a i n in v i t r o t est s y st em s . A t t r a ce lev el s in food s, M C P D is con si d er ed n ot t o p os e a ca rcin ogen ic r i sk t o h u m a n s .K e y w o r d s ca r cin og en icit y, ch lor oh yd r in , 3 -ch lor o-1 ,2 -p r op a n ed iol, ge n ot oxicit y, h or m on a l in d u ct ion , L e yd ig ce ll C h e m ica ls in t h e food s u p p ly a r e r e g u la t e d w it h r e s p e ct t o t h eir t oxicolog ica l e ffe ct a n d t h e a n t icip a t e d e x p os u r e le v e ls in t h e p op u la t ion . Am on g t h e cr it e r ia t h a t ch a r a ct e r ize t h e p ot en t ia l a d v er s e e ffe ct of a ch e m ica l in food is it s cla s s i® ca t ion a s n on ca r cin oge n , g e n ot oxic ca r -In t e r n a t i o n a l J o u r n a l o f To x i c o l o g y, 1 7 :4 7 ± 7 6 , 1 9 9 8 47 C o p y r i g h t Ó 1 9 9 8 Ta y l o r & F r a n c i s 1 0 9 1 -5 8 1 8 /9 8 $ 1 2 .0 0 + .0 0

Sucralose is a non-caloric high intensity sweetener that is approved globally for use in foods and beverages. This review provides an updated summary of the literature addressing the safety of use of sucralose. Studies reviewed include chemical characterization and stability, toxicokinetics in animals and humans, assessment of genotoxicity, and animal and human feeding studies. Endpoints evaluated include effects on growth, development, reproduction, neurotoxicity, immunotoxicity, carcinogenicity and overall health status. Human clinical studies investigated potential effects of repeated consumption in individuals with diabetes. Recent studies on the safety of sucralose focused on carcinogenic potential and the effect of sucralose on the gut microflora are reviewed. Following the discovery of sweet taste receptors in the gut and studies investigating the activation of these receptors by sucralose lead to numerous human clinical studies assessing the effect of sucralose on overall glycemic control. Estimated daily intakes of sucralose in different population subgroups, including recent studies on children with special dietary needs, consistently find that the intakes of sucralose in all members of the population remain well below the acceptable daily intake. Collectively, critical review of the extensive database of research demonstrates that sucralose is safe for its intended use as a non-caloric sugar alternative.

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Palmitoylethanolamide (PEA) is a natural fatty acid amide found in a variety of foods, which was initially identified in egg yolk. MicroPEA of defined particle size (0.5–10 μm) was evaluated for mutagenicity in Salmonella typhimurium, for clastogenicity/aneuploidy in cultured human lymphocytes, and for acute and subchronic rodent toxicity in the rat, following standard OECD test protocols, in accordance with Good Laboratory Practice (GLP). PEA did not induce mutations in the bacterial assay using strains TA1535, TA97a, TA98, TA100, and TA102, with or without metabolic activation, in either the plate incorporation or liquid preincubation methods. Similarly, PEA did not induce genotoxic effects in human cells treated for 3 or 24 h without metabolic activation, or for 3 h with metabolic activation. PEA was found to have an LD50 greater than the limit dose of 2000 mg/kg body weight (bw), using the OECD Acute Oral Up and Down Procedure. Doses for the 90‐day rat oral toxicity study were based on results from the preliminary 14‐day study, that is, 250, 500, and 1000 mg/kg bw/day. The No Effect Level (NOEL) in both subchronic studies was the highest dose tested.

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