1. Rajaa Bellaje Laboratory of Genetics and Biometry Faculty of Science, University Ibn Tofail, Kenitra, Morocco Poisoning by lightening creams in Morocco epidemiological profile August 2015

2. Introduction Historic :  The practice of skin lightening takes soaring in South Africa.  The phenomenon has become widespread over the last 20 years (the Maghreb, the Middle East, the Caribbean, the American continent (United States of America, South America, Central America) and Asia (India, Philippines)).

3. Introduction:  Cutaneous and systemic complications of poisoning by skin lightening products have been reported in several studies (2,3, 8).  In Morocco, skin lightening products (especially contraband products of unknown composition) were incriminated in 14 % of cases of poisoning by cosmetic products Reported to Pharmacovigilance and Poison Control Center(1).  The majority of cases reported in Morocco are due to the accidental or voluntary ingestion of the offending skin products. Toxicity of skin whitening products : Toxicity of skin whitening products :

4. objective  Establish the epidemiology of poisoning skin lightening creams reported to Poison Control and Pharmacovigilance Center of Morocco.

5. Data and Methods : Type of study:  This is a retrospective descriptive study of cases of poisoning by skin lightening products, reported between 1992 and 2008 at the poison control center and pharmacovigilance of Morocco (95 cases).

6. Data and Methods : Data and Methods : Collection of toxicological information Declaration on standardized plugs toxicovigilance from health structures Toxicological information or telephone answering, recorded on medical record by the duty Doctor centralization and computerization of information in a data base Data collection Data collection

7. Data and Methods Data analysis Data analysis  The parameters studied are epidemiological (age and sex of the patient, location and type of intoxication), clinical, evaluative (gradation) and evolutionary. Statistical analysis was done using the software Epi Info Version 3.2.2.

8. Results Description of the population(1): Description of the population(1):  Sex-ratio (F/M) =1,73 (F=59, M=34)  Mean age = 20 years old ± 1.4 [1-70 years old] o Mean age of male victims=19 years old ± 3years old o Mean age of female victims =22 years old ± 2years old t = 0,948, p>0,05

9. Results  Age class of patients: Description of the population(2):

10. Results Description of the population(3):

11. Description of the population(4): Description of the population(4):  Origin of intoxicated: o Urban : 83 cases (88,83%), o Rural : 11 cases (11,7%)  Type of intoxication: o Isolated : 92 cases (96,8%) o Collective : 3 cases (3,2%)  Place of intoxication: o Domicile: 90 cases (90%) o Professional: 1 cases (1%) Results

12. Results Type of exposure (n=93)Nbre of cases (%) voluntary intoxication: Suicide attempt accidental intoxication: Classical Professional 31(33,3) 62(66,7) 61(65,6) 1(1,1) Description of the population(5): Description of the population(5):  Circumstances of poisoning:  Route of poisoning: o Oral: 90 cases (95%) o Inhalation: 4 cases (4%) o Cutaneaous: 1case (1%)

13. Results  gradation (gravity score):  Evolution : Favorable : 95 cases(100%) Sequelae: 1 case Sequelae: 1 case

14. Results Individual characteristics studied Intoxication circumstances: Accidental Voluntary Total n (%)p Âge 1- 4 years old 5 - 14 years old 15 - 19 years old ≥ 20 years old Total 16(100) - 8(80) 2(20) 15(62,5) 9(37,5) 23((53,49) 20(46,51) 62 31 16(100) 10(100) 24(100) 43(100) 93 <0,01 Sex Female Male Total 31(54,39) 26(45,61) 29(85,29) 5(14,71) 60 31 57(100) 34(100) 91 <0,01 Gradation: Grade 0 Grade 1 Grade 2 Grade 3 Total 2(100) - 3(75) 1(25) 49(67,12) 24(32,88) 2(66,67) 1(33,33) 56 26 2(100) 4(100) 73(100) 3(100) 82 >0,05 Distribution of cases of poisoning according to circumstances, severity of intoxication, age and sex of the intoxicated. Distribution of cases of poisoning according to circumstances, severity of intoxication, age and sex of the intoxicated.

15. Results Clinical manifestations (symptomatology in 74 cases)Nbre n(%) Affections of the gastrointestinal system: Vomiting Nausea Digestive pain Diarrhea Hematemesis 68(92) 47(63,5) 36(48,6) 32(43,2) 4(5,4) 1(1,35) Nervous system disorders: Cephalalgia Vertige State of agitation Sensory disorder Convulsion Coma 33(44,6) 16(48,5) 23 (31,1) 2(2,7) 1(1,35) Symptomatology(1) Symptomatology(1)

16. Results Clinical manifestations (symptomatology in 74 cases)Nbre n(%) Cardiovascular disorders: Hypotension Heart rhythm disorders: - Tachycardia - Bradycardia - Arrhythmia 14(18,9) 6(8,11) 9(12,16) 8 (10,8) 1(1,35) 2(2,7) Respiratory disorder: Dyspnea Apnea 6(8,11) 5(6,75) 1(1,35) Others: Asthenia Dehydration 8(10,8) 7(9,45) 1(1,35) Symptomatology(2) Symptomatology(2)

17. Discussion  The high consumption and easy accessibility to cosmetic products by the female would explain her prevalence recorded in our series of study.  The women predominate suicide attempts reported in our series of study the woman often seeks a suicide method «softer» allowing to have a significant chance of survival.  Young children represent the majority of cases of accidental poisoning by oral route. The acquisition of a certain autonomy of movement and oral exploration of what surrounds in this age group would be the most probable explanation.  Male dominance linked to this age has been reported in several studies. This situation is explained by the physical and psychological characteristics specific to the boy : greatest curiosity, desire for independence, aggressiveness and turbulence that expose more accidents than the girl. Characteristic of the population

18.  Certain clinical signs reported in our study series might be a consequence of poisoning by depigmentation products containing hydroquinone associated or not with other toxic compounds.  Hydroquinone has remained for many years a reference in terms of depigmentation agents. Hydroquinone = Benzène-1.4-diol. Discussion Symptomatology(1 ) Symptomatology(1 ) Suspected molecule: Hydroquinone Inhibition of melanogenesis through tyrosinase deleting Release of toxic free radicals for melanosome Depigmenting power

19. Discussion Local toxicity: Studies Studies  Several manifestations of dyschromic dermatitis have been described during cutaneous application of lightening products containing hydroquinone: the periorbital hyperchromia Exogenous ochronosis Irritative or allergic dermatitis Contact  In Morocco, the use of hydroquinone as a bleaching molecule had been banned since 2004 because of its adverse effects such as skin irritation, contact allergies, acne and depigmentation.  In our series of study, all the symptoms observed were occurred during oral intoxication by depigmenting products. Symptomatology(2) Symptomatology(2) Suspected molecule: Hydroquinone

20. Discussion Systemic Toxicity: Studies Studies  Acute intoxication with hydroquinone causes in animals, neurological and muscular complications, tremors, convulsions and death in 2 hours after respiratory distress.  In humans, a case of epilepsy was reported in a child who ingested a solution depigmenting containing 2% hydroquinone (1).  Since 2001, the incorporation of hydroquinone in cosmetic products is forbidden in Europe (European regulation 76/768 / EEC and 84/415 / EEC) because of the many dermatological and systemic complications (general) that its use entails. (1) Burns JM1, Marino A, Manno M, Rhyee S, Bover Ew. Status epilepticus in a child secondary to ingestion of skin-lightening cream. (Pediatric Emerg Care). 2013 May;29(5):662-4. Symptomatology(3) Symptomatology(3) Suspected molecule: Hydroquinone

21.  Once absorbed by the body, hydroquinone is widely distributed in tissues and is metabolized in the liver and the gastrointestinal tract to1,4-benzoquinone and other oxidized compounds.  The oxidized derivatives bind to various biological compounds such as proteins and DNA, act on cell metabolism and contribute to toxicity.  Recently, a study reported hydroquinone inhibitory effect on the enzyme acetylcholineserase (1). The inhibition of acetycholinesterase may explain one hand the occurrence of specific symptoms in acute poisoning by hydroquinone including neurological signs. (1) Scozzafaya A, Kalin P, Supuran CT, Gulcini, Alwasel SH. The impact of hydroquinone on acetylcholine esterase and certain human carbonic anhydrase isoenzymes (hCA I, II, IX, and XII). J EnZyme Inhib Med Chem. 2015 Jan 14:1-6. Discussion Mechanism of toxicity: Mechanism of toxicity: Symptomatology(4) Symptomatology(4) Suspected molecule: Hydroquinone

22. Discussion Mechanism toxicity: inhibition of Acetylcholinesterase:  Role of Acetylcholinesterase: It’s serine protease, responsible for acetylcholine( Ach) hydrolysis and plays a fundamental role in impulse transmission by terminating the action of the neurotransmitter Ach at the cholinergic synapses and neuromuscular junction. Symptomatology(5) Symptomatology(5) Inhibition of d’Acetylcholinaste accumulation of Ach

23. Acute exposure to cholinesterase inhibitors often cause a cholinergic crisis characterized by: Discussion Symptomatology(6) Symptomatology(6) Suspected molecule: Hydroquinone Mechanism toxicity: inhibition of Acetylcholinesterase :  Symptomatology: Muscle weakness Muscle weakness Tiredness, Tiredness, Muscle cramps, Muscle cramps, paralysis paralysis Neuromuscular junction:

24. Discussion Symptomatology(7) Symptomatology(7) Suspected molecule: Hydroquinone Mechanism toxicity: inhibition of Acetylcholinesterase :  Symptomatology: Anxiety Anxiety Cephalalgia Cephalalgia Convulsion Convulsion Respiratory depression Respiratory depression Asthenia Asthenia Coma Coma système nerveux central: :

25. Discussion Symptomatology(8) Symptomatology(8) Suspected molecule: Hydroquinone Mechanism toxicity: inhibition of Acetylcholinesterase :  Symptomatology: tachycardia tachycardia hypertension hypertension Sympathetic system

26. Discussion Symptomatology(9) Symptomatology(9) Suspected molecule: Hydroquinone Mechanism toxicity: inhibition of Acetylcholinesterase :  Symptomatology: Trouble visuel Trouble visuel Bradycardie Bradycardie Hypotension Hypotension Salivation Salivation Paraympathetic system

27. Conclusions  In Morocco, there is no adequate or effective system cosmetovigilance the majority of cosmetic products found in markets escapes any regulation.  Lightening contraband products even contain pesticides are freely sold in grocery stores, markets and perfumeries  It is therefore essential to establish regulations in our country to the manufacture and marketing of these products  A ministerial decision for implementation of the new circular recording of cosmetic products to the Poison Control Center and Pharmacovigilance before being placed on the market will ensure certainly better orientation of support in case of declaration of intoxication.

28. Thank you for your attention